CN106432126B - 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method - Google Patents

1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method Download PDF

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CN106432126B
CN106432126B CN201610826407.9A CN201610826407A CN106432126B CN 106432126 B CN106432126 B CN 106432126B CN 201610826407 A CN201610826407 A CN 201610826407A CN 106432126 B CN106432126 B CN 106432126B
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unsubstituted
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perfluoroalkyl
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CN106432126A (en
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莫冬亮
邹宁
陈春华
冯钰�
苏桂发
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Guangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a series of 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic methods.1- oxygen -2 of the present invention, 8- diazacyclo nonane derivatives have the structure as shown in following formula (I), its synthetic method are as follows: take compound shown in the compound as shown in following formula (II) and formula (III), it is 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.The compound difference of structure shown in the formula (I), formula (II) and formula (III) is as follows:R6N=C=X (III).

Description

1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of 1- oxygen -2,8- diazacyclo nonane derivatives and its conjunction At method.
Background technique
Diazacyclo nonane skeleton is core skeleton important in natural products and drug molecule, is important physiological activity Unit, it is antitumor, in terms of have important application.Since diaza nine-atomic ring skeleton is always in organic synthesis Difficult point and challenge, so that the application of this kind of compound is limited by very large.The plan of this nine circle heterocyclic rings skeleton is synthesized at present Slightly can by the tandem reaction of palladium chtalyst (R.Shintani, K.Ikehata, T.Hayashi, J.Org.Chem.2011,76, 4776-4780), multi-component tandem reaction (A.F.De la Torre, D.G.Rivera, O.Concepci ó n, R.Echemendia, A.G.Correa, M.W.Paixao, J.Org.Chem.2016,81,803-809) etc., but these methods are all The deficiencies of it is limited that there are substrates, and functional group compatibility is poor, and more complex using raw material.
Summary of the invention
It is derivative that the technical problem to be solved in the present invention is to provide a series of 1- oxygen -2,8- diazacyclo nonanes of structure novels Object and their synthetic method.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salts:
Wherein:
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son；
X indicates oxygen or sulphur atom.
In above compound:
R1Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R2Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R3Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R4Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R5Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R6Further preferably hydrogen or C1~12Alkyl or unsubstituted, monosubstituted or disubstituted phenyl.
The synthetic method of compound shown in above-mentioned formula (I), mainly comprises the steps that and takes the compound as shown in following formula (II) It with compound shown in formula (III), is placed in organic solvent, reacts in the presence of oxygen, object crude product is made；
Wherein:
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son；
X indicates oxygen or sulphur 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 formula (II) is N- alkenyl α, and β-unsaturation nitrone derivative 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) synthesized, can also free design synthetic route synthesized, herein No longer it is described in detail.And compound shown in formula (III) is isocyanide ester or isothiocyanate, directly can commercially be obtained (such as Phenyl isonitrile acid, isobutyl group isocyanide ester, benzyl isocyanide ester, phenyl isothiocyanate etc.)
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.
In above-mentioned synthetic method, reaction, which is typically chosen under air conditions, to be carried out, and simultaneous reactions are preferably being lower than 100 DEG C Under conditions of carry out, be further preferred that under conditions of room temperature is to 80 DEG C and carry out, more preferably carried out under conditions of 80 DEG C. Whether reaction can be used TLC tracing detection completely.According to the experience of applicant, when reaction carries out under the conditions of room temperature is to 80 DEG C When, reaction time control is more suitable 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 1.0:1.0~5.0.The use of the organic solvent Amount is advisable with that can dissolve the raw material participated in and reacted, it is generally the case that on the basis of compound shown in the formula (II) of 1mmol, institute There is the raw material for participating in reaction usually to be dissolved with the organic solvent of 1~10mL.
Prepared by the above method is the crude product of formula (I) compound, and existing conventional purification process can be used and carry out to it It purifies to improve the purity of formula (I) compound.Generally use silica gel thin-layer chromatography or silica gel column chromatography, or the side of recrystallization Formula is purified, and the eluant, eluent in chromatography is identical with solvent when recrystallization, can be by petroleum ether and ethyl acetate By the mixed solvent that the volume ratio of 10:1~1:1 forms, it is also possible to the volume by n-hexane and ethyl acetate by 10:1~1:1 Than the mixed solvent of composition, the mixed solvent being made of petroleum ether and methanol by the volume ratio of 100:1~10:1 can also be, again The mixed solvent being either made of methylene chloride and methanol by the volume ratio of 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.
Compared with prior art, it is derivative that the present invention provides a series of 1- oxygen -2,8- diazacyclo nonanes of structure novels Object and its 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.
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 α involved in following embodiment, β-unsaturation nitrone derivative (i.e. compound shown in formula (II)) ginseng It is synthesized according to following synthetic routes:
Wherein,
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom.
By Cu (OAc)2(0.3mmol, 54mg), α, β-unsaturated oxime substrate S1 (0.3mmol) and ene boric acid S2 (0.9mmol) is placed in reaction tube, and 3mL1 is added, and pyridine (3mmol, 0.24mL) is added at room temperature in 2- dichloroethanes；At 25 DEG C It is lower stirring 12~for 24 hours, gained reactant be added water (10mL), be extracted with dichloromethane (2 × 10mL), merge organic phase, with nothing It is filtered after aqueous sodium persulfate is dry, solvent is removed under reduced pressure, silica gel column chromatography separation on residue (petrol ether/ethyl acetate=10:1~ 1:1, volume ratio), obtain target product 1 (i.e. compound N shown in formula (II)-alkenyl α, β-unsaturation nitrone).
Isocyanide ester involved in following embodiment or isothiocyanate (i.e. compound shown in formula (III)) are from city It is directly commercially available on field.
Embodiment 1
1- oxygen -2,8- diazacyclo nonane derivatives of the present invention are synthesized by following synthetic routes.
Wherein,
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son.
By N- alkenyl α, β-unsaturation nitrone substrate 1 (0.3mmol), isocyanide ester 2 (0.9mmol) are placed in reaction tube, 3mL dimethyl sulfoxide is added, 5-20h is stirred to react at 80 DEG C, gained reactant is added water (10mL), is extracted with dichloromethane (2 × 10mL) merges organic phase, with filtering after anhydrous sodium sulfate drying, solvent is removed under reduced pressure, silica gel column chromatography separates on residue (petrol ether/ethyl acetate=10:1~1:1, volume ratio), obtains target product 3.It different target products and its is characterized as below:
3a: solid, 66mg, 76%yield；mp 100-102℃.1H NMR(400MHz,CDCl3):δ7.35–7.29 (m, 2H), 7.23 (t, J=6.5Hz, 3H), 7.19-7.07 (m, 7H), 7.01 (d, J=8.3Hz, 2H), 6.40 (q, J= 16.1Hz, 2H), 5.92 (d, J=10.9Hz, 1H), 3.83 (d, J=10.9Hz, 1H), 2.66 (q, J=7.4Hz, 1H), 2.20 (s, 3H), 1.99 (s, 3H), 1.39 (d, J=7.4Hz, 3H)；13C NMR(100MHz,CDCl3):δ177.3,154.1, 143.7,137.2,136.2,135.5,134.5,130.1,128.4,128.4,127.9,127.5,126.8,126.2, 125.6,125.4,124.3,123.3,46.8,44.6,20.1,19.9,13.1；IR(neat):3453,3036,2928, 1731,1634,1509,969,695cm-1；MS(ESI)m/z[M+H]+calcd for[C29H29N2O2]+:437.2229； Found:437.2230. its structural formula is as follows:
3b: solid, 40mg, 40%yield；mp 96-97℃.1H NMR(400MHz,CDCl3):δ7.19–7.08(m, 4H), 7.04 (dd, J=10.7,8.0Hz, 2H), 6.99 (d, J=8.3Hz, 2H), 6.87-6.79 (m, 2H), 6.67 (d, J= 8.8Hz, 2H), 6.35-6.22 (m, 2H), 5.82 (d, J=10.9Hz, 1H), 4.08-3.95 (m, 1H), 3.72 (s, 3H), 3.65 (s, 3H), 2.60 (q, J=7.4Hz, 1H), 2.17 (s, 3H), 1.95 (d, J=4.3Hz, 3H), 1.34 (d, J= 7.4Hz,3H).13C NMR(100MHz,CDCl3):δ160.2,158.6,150.6,150.1,135.9,135.6,134.8, 133.6,130.5,130.1,129.5,129.1,128.2,125.0,124.3,121.4,114.4,114.1,56.7,56.1, 51.7,45.6,21.1,18.4,16.2.IR(neat):3451,3032,2924,2850,1733,1606,1510,968, 635cm-1；MS(ESI)m/z[M+H]+calcd for[C31H33N2O4]+:497.2440；Found:497.2470. its structural formula It is as follows:
3c: solid, 67mg, 59%yield；mp 98-99℃.1H NMR(400MHz,CDCl3): δ 7.60 (d, J= 8.2Hz, 2H), 7.41 (d, J=8.3Hz, 2H), 7.36 (d, J=8.1Hz, 2H), 7.23 (d, J=8.2Hz, 2H), 7.11 (d, J=8.5Hz, 2H), 7.05 (d, J=8.4Hz, 2H), 6.52 (d, J=16.0Hz, 1H), 6.40 (d, J=16.0Hz, 1H), 5.95 (d, J=10.9Hz, 1H), 3.92 (d, J=10.9Hz, 1H), 2.64 (q, J=7.4Hz, 1H), 2.22 (s, 3H), 2.02 (s, 3H), 1.42 (d, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3):δ178.3,155.2,148.6,140.1, 138.9,137.2,136.2,130.5,129.9,129.5,127.8,127.4,126.9,12 6.8 (d, J=15Hz), 125.8 (d, J=15Hz), 47.7,45.9,30.0,21.4,21.2,14.4.IR (neat): 3446,3047,2925,1730,1624, 1511,966,685cm-1；MS(ESI)m/z[M+H]+calcd for[C31H27F6N2O2]+:573.1977；found: 573.1963. its structural formula is as follows:
3d: solid, 72.5mg, 61%yield；mp 153-154℃.1H NMR(500MHz,CDCl3): δ 7.42 (d, J= 8.4Hz, 2H), 7.25 (d, J=8.5Hz, 2H), 7.12-7.03 (m, 4H), 6.98 (m, 4H), 6.38 (d, J=16.0Hz, 1H), 6.27 (d, J=16.0Hz, 1H), 5.84 (d, J=10.9Hz, 1H), 3.76 (d, J=10.9Hz, 1H), 2.70 (q, J= 7.4Hz, 1H), 2.18 (s, 3H), 1.97 (s, 3H), 1.33 (d, J=7.4Hz, 3H)；13C NMR(125MHz,CDCl3):δ 178.7,155.6,144.1,138.9,137.5,136.3,135.9,133.1,132.2,130.8,130.1,129.3, 128.9,128.5,126.4,124.7,122.3,121.7,48.2,45.7,21.8,21.6,14.6.IR(neat):3433, 3022,2919,2858,1722,1632,1486,974,658cm-1；MS(ESI)m/z[M+H]+calcd for [C28H27Br2N2O2]+:593.0439；Found:593.0432. its structural formula is as follows:
3e: solid, 34mg, 52%yield；mp 93-94℃.1H NMR(500MHz,CDCl3):δ7.64–7.50(m, 2H), 7.46-7.31 (m, 3H), 7.14 (s, 4H), 5.10 (d, J=10.8Hz, 1H), 3.18-3.15 (m, 2H), 2.43 (q, J =7.4Hz, 1H), 2.10 (s, 3H), 1.93 (s, 3H), 1.33 (d, J=7.4Hz, 3H)13C NMR(125MHz,CDCl3):δ 156.2,152.3,138.4,136.8,136.0,134.8,132.3,130.5,130.3,130.2,125.5,122.6,36.7, 33.6,22.4,19.9,18.8.IR(neat):3426,3014,2927,2846,1713,1647,1467,989,654cm-1；MS (ESI)m/z[M+H]+calcd for[C21H23N2O2]+:335.1760；Found:335.1743. its structural formula is as follows:
3f: solid, 51mg, 56%yield；mp 165-166℃.1H NMR(400MHz,CDCl3): δ 8.21 (d, J= 8.4Hz, 2H), 7.44 (d, J=8.7Hz, 2H), 7.25-7.23 (m, 2H), 7.17-7.09 (m, 3H), 6.97 (d, J= 8.3Hz, 2H), 6.91 (d, J=8.3Hz, 2H), 5.85 (d, J=10.8Hz, 1H), 4.06 (d, J=10.8Hz, 1H), 2.62 (q, J=7.4Hz, 1H), 2.13 (s, 3H), 2.03 (s, 3H), 1.38 (d, J=7.4Hz, 3H)13C NMR(100MHz, CDCl3):δ178.4,155.3,152.4,147.4,141.4,136.8,136.6,136.0,129.7,128.7,128.7, 127.9,127.4,125.2,125.1,123.8,47.1,46.2,21.5,21.2,14.4.IR(neat):3451,2959, 2925,2859,1740,1640,1513,984,754,693cm-1；MS(ESI)m/z[M+H]+calcd for[C27H26N3O4]+: 456.1923；Found:456.1919. its structural formula is as follows:
3g: solid, 38mg, 54%yield；mp 96-97℃.1H NMR(500MHz,CDCl3):δ7.79–7.64(m, 2H), 7.59-7.43 (m, 3H), 7.32-7.20 (m, 4H), 5.12 (d, J=12.4Hz, 1H), 3.16 (s, 3H), 2.34 (s, 3H), 2.20-1.87 (m, 1H), 1.59-1.32 (m, 1H), 1.08-1.06 (d, J=10.1,3H), 1.05-1.03 (d, J= 10.1,3H)；13C NMR(125MHz,CDCl3):δ157.5,152.3,137.8,136.9,136.5,136.1,132.1, 130.5,130.4,130.1,125.2,45.1,35.9,22.2,19.7,19.1,14.5.IR(neat):3453,2961, 2865,1746,1654,1503,980,694cm-1；MS(ESI)m/z[M+H]+calcd for[C22H25N2O2]+:349.1916； Found:349.1925. its structural formula is as follows:
3h: solid, 37mg, 46%yield；mp 99-100℃.1H NMR(500MHz,CDCl3):δ7.45–7.41(m, 1H), 7.34-7.28 (m, 3H), 7.33 (s, 4H), 5.49 (d, J=12.5Hz, 1H), 2.85 (dd, J=22.2,12.4Hz, 1H), 2.65 (s, 3H), 2.44 (s, 3H), 2.33-2.23 (m, 1H), 1.14 (d, J=12.8Hz, 1H)；13C NMR(125MHz, CDCl3):δ153.3,152.4(,144.4,137.8,133.9,131.6,131.0,128.8,126.1,124.5,122.4, 120.3,111.9,53.1,47.8,23.1,20.5,18.2.IR(neat):3442,2978,2858,1739,1649,1505, 973,691cm-1；MS(ESI)m/z[M+H]+calcd for[C22H22F3N2O2]+:403.1633；Found:403.1654. it is tied Structure formula is as follows:
3i: solid, 63mg, 63%yield；mp 104-105℃.1H NMR(500MHz,CDCl3):δ7.94–7.85(m, 2H), 7.53-7.45 (m, 5H), 7.38-7.26 (m, 6H), 7.26-7.15 (m, 6H), 6.76 (d, J=16Hz, 1H), 6.50 (d, J=16Hz, 1H), 5.51 (d, J=12.5Hz, 1H), 3.85 (d, J=12.5Hz, 1H), 3.53 (q J=7.5Hz, 1H), 2.27 (s, 3H), 1.19 (d, J=13.0Hz, 3H)；13C NMR(125MHz,CDCl3):δ142.9,136.6,136.5, 135.7,135.4,134.5,130.6,130.7,129.8,129.7,129.7,129.2,128.8,128.6,128.5, 128.3,48.3,42.8,21.3,15.2.IR(neat):3458,3048,2930,1754,1623,1521,956,698cm-1； MS(ESI)m/z[M+H]+calcd for[C34H31N2O2]+:499.2386；Found:499.2364. its structural formula is as follows:
3j: solid, 54mg, 58%yield；mp 103-104℃.1H NMR(400MHz,CDCl3):δ7.36–7.25(m, 2H), 7.26-7.18 (m, 2H), 7.15-7.04 (m, 7H), 6.99 (d, J=8.2Hz, 2H), 6.42 (d, J=16Hz, 1H), 6.37 (d, J=16Hz, 1H), 5.96 (d, J=11.0Hz, 1H), 3.74 (d, J=11.0Hz, 1H), 2.56-2.38 (m, 2H), 2.16 (s, 3H), 2.01-1.86 (m, 2H), 1.04 (t, J=7.4Hz, 3H), 0.94 (t, J=7.4Hz, 3H)；13C NMR (100MHz,CDCl3):δ181.6,155.4,144.8,138.1,137.3,136.6,135.6,131.1,129.6,129.4, 128.8,128.5,127.8,127.2,126.7,126.5,125.6,124.5,53.4,46.6,30.6,23.5,20.94, 13.4,10.8.IR(neat):3452,3039,291,1735,1638,152,981,693cm-1；MS(ESI)m/z[M+H]+ calcd for[C27H33N2O2]+:417.2542；Found:417.2561. its structural formula is as follows:
3k: solid, 56mg, 61%yield；mp 81-82℃.1H NMR(400MHz,CDCl3)δ7.32–7.18(m, 5H), 7.17-7.12 (m, 4H), 7.10-7.02 (m, 3H), 6.97 (d, J=8.3Hz, 2H), 6.49 (d, J=16.0Hz, 1H), 6.38 (d, J=16.0Hz, 1H), 6.14 (d, J=11.3Hz, 1H), 4.06 (d, J=11.3Hz, 1H), 2.69-2.66 (m, 1H), 2.61-2.58 (m, 1H), 2.16 (s, 1H), 2.11-1.99 (m, 2H), 1.79 (d, J=13.4Hz, 1H), 1.69 (dd, J =12.7,3.7Hz, 1H), 1.50 (d, J=13.6Hz, 1H), 1.37-1.27 (m, 1H)；13C NMR(100MHz,CDCl3):δ 180.8,156.0,143.4,139.7,137.1,136.8,135.5,131.4,129.7,129.4,128.9,128.7, 128.0,127.7,127.4,126.7,125.2,123.9,55.1,44.8,35.8,30.9,30.2,26.9,21.1.IR (neat):3442,3035,2934,2853,1726,1636,1494,1444,1379,983,692cm-1；MS(ESI)m/z[M+ H]+calcd for[C31H31N2O2]+:462.2307；Found:462.2316. its structural formula is as follows:
3l: solid, 41mg, 50%yield；mp 93-94℃.1H NMR(400MHz,CDCl3):δ7.34–7.30(m, 2H), 7.29-7.24 (m, 3H), 7.24-7.13 (m, 5H), 6.54 (d, J=16.1Hz, 1H), 6.49 (d, J=16.1Hz, 1H), 5.76 (d, J=10.8Hz, 1H), 3.99-3.81 (m, 1H), 3.70 (d, J=10.8Hz, 1H), 3.19-2.94 (m, 1H), 2.64-2.43 (m, 1H), 1.96 (s, 3H), 1.77-1.53 (m, 1H), 1.35 (s, 1H), 1.30 (d, J=7.4Hz, 3H),1.26(s,1H).
13C NMR(100MHz,CDCl3):δ177.4,154.8,1440,137.3,135.4,129.1,128.3,127.7, 127.2,127.0,126.1,125.6,125.5,124.2,46.6,45.1,45.0,28.6,20.3,19.0,12.8, 12.7.IR(neat):3439,3031,2926,2858,1723,1631,1493,1450,1383,972,697cm-1；MS(ESI) m/z[M+H]+calcd for[C26H31N2O2]+:403.2385；Found:403.2377. its structural formula is as follows:
3m: solid, 52mg, 60%yield；mp 89-90℃.1H NMR(500MHz,CDCl3):δ7.38–7.34(m, 2H), 7.30-7.26 (m, 4H), 7.22-7.11 (m, 4H), 7.10-7.04 (m, 3H), 6.63 (d, J=16.1Hz, 1H), 6.54 (d, J=16.1Hz, 1H), 6.42-6.34 (m, 2H), 5.61 (d, J=10.7Hz, 1H), 5.16 (d, J=14.2Hz, 1H), 4.17 (d, J=14.2Hz, 1H), 3.16 (d, J=10.7Hz, 1H), 2.48 (q, J=7.4Hz, 1H), 1.92 (s, 3H), 1.26 (d, J=7.4Hz, 3H)13C NMR(125MHz,CDCl3):δ178.6,156.1,144.3,137.2,136.7,136.4, 130.4,129.9,129.6,128.8,128.7,128.6,128.1,127.8,126.7,126.6,126.6,125.0,49.4, 46.7,45.7,21.3,14.1.IR(neat):3448,3035,2927,2862,1719,1634,1495,973,698cm-1；MS (ESI)m/z[M+H]+calcd for[C29H29N2O2]+:437.2229；Found:437.2222. its structural formula is as follows:
3n: solid, 25mg, 29%yield；mp 67-68℃.1H NMR(500MHz,CDCl3):δ7.46–7.43(m, 2H), 7.42-7.35 (m, 4H), 7.32-7.27 (m, 4H), 6.74 (d, J=16.0Hz, 1H), 6.65 (d, J=16.0Hz, 1H), 5.87 (d, J=10.9Hz, 1H), 3.80-3.78 (m, 1H), 3.38-3.33 (m, 1H), 2.61 (q, J=7.4Hz, 1H), 2.30-2.37 (m, 1H), 2.06 (s, 3H), 1.96 (d, J=6.2Hz, 1H), 1.85-1.80 (m, 3H), 1.59 (d, J= 4.7Hz, 1H), 1.48-1.44 (m, 1H), 1.38 (d, J=7.4Hz, 3H)；13C NMR(125MHz,CDCl3):δ178.2, 155.3,144.9,140.0,136.6,129.4,129.4,128.7,127.9,127.7,127.1,127.0,126.6, 126.6,59.8,48.2,45.4,29.8,29.3,26.4,26.2,25.3,21.3,13.7.IR(neat):3437,3034, 2928,2858,1720,1635,1494,984,696cm-1；MS(ESI)m/z[M+H]+calcd for[C28H33N2O2]+: 429.2542；Found:429.25394. its structural formula is as follows:
3o: solid, 84mg, 76%yield；mp 84-85℃.1H NMR(500MHz,CDCl3):δ7.66–7.62(m, 2H), 7.44-7.41 (M, 3H), 7.37-7.27 (m, 4H), 7.26-7.20 (m, 3H), 7.13 (d, J=8.9Hz, 2H), 6.55 (d, J=16.0Hz, 1H), 6.42 (d, J=16.0Hz, 1H), 6.08 (d, J=11.0Hz, 1H), 3.89 (d, J=11.0Hz, 1H), 2.79 (q, J=7.5Hz, 1H), 2.11 (s, 3H), 1.50 (d, J=7.4Hz, 3H)13C NMR(125MHz,CDCl3):δ 178.53 (s), 154.86 (s), 146.14 (s), 144.35 (s), 139.72 (s), 137.89 (d, J=2.1Hz), 136.20 (s),131.44(s),129.75(s),129.50(s),128.62(s),128.04(s),127.36(s),126.61(s),, 126.15(s),124.85(s),117.29(s),90.09(s),47.91(s),21.13(s),14.10(s).IR(neat): 3450,3029,2939,2868,1719,1634,1515,983,692cm-1；MS(ESI)m/z[M+H]+calcd for [C28H26IN2O2]+:549.1039；Found:549.1034. its structural formula is as follows:
3p: solid, 53mg, 59%yield；mp 96-97℃.1H NMR(500MHz,CDCl3):δ7.58-7.53(dm, 2H), 7.45-7.35 (m, 6H), 7.34-7.25 (m, 2H), 7.20 (t, J=3.0Hz, 1H), 6.83 (t, J=16.5Hz, 3H), 6.55 (d, J=16.0Hz, 1H), 6.42 (d, J=16.0Hz, 1H), 6.46 (d, J=30.2Hz, 1H), 5.51 (d, J= 12.5Hz,1H),3.33(s,3H),3.21-3.13(m,1H),2.30(s,3H),2.25(s,3H)2.20-2.10(m,1H), 1.35 (d, J=13.0Hz, 3H)13C NMR(125MHz,CDCl3):δ151.8,151.1,142.8,139.4,136.9, 135.7,135.3,130.5,129.3,128.9,128.6,128.3,128.2,127.8,126.3,124.3,124.1, 120.8,53.6,47.3,22.5,17.8,16.4.IR(neat):3447,3028,2922,2871,1731,1606,1323, 1265,965,693cm-1；MS(ESI)m/z[M+H]+calcd for[C30H31N2O2]+:451.2386；found:451.2368. Its structural formula is as follows:
3q: solid, 61mg, 68%yield；mp 102-103℃.1H NMR(400MHz,CDCl3):δ7.61–7.55(m, 2H), 7.46-7.37 (m, 6H), 7.37-7.25 (m, 6H), 6.86 (d, J=16Hz, 1H), 6.58 (d, J=16Hz, 1H), 5.98 (d, J=12.5Hz, 1H), 3.30 (d, J=12.5Hz, 1H), 3.17 (s, 3H), 2.37 (s, 3H), 0.99 (s, 3H), 0.95(s,3H)；13C NMR(100MHz,CDCl3):δ166.3,152.7,142.5,137.6,136.7,136.6,134.5, 132.8,131.9,130.4,129.6,128.9,128.7,128.2,127.4,126.6,125.5,125.2,59.3,45.3, 26.3,22.4,22.1；IR(neat):3456,3032,2921,1742,1638,1501,985,692cm-1；MS(ESI)m/z[M +H]+calcd for[C30H31N2O2]+:451.2386；Found:451.2391. its structural formula is as follows:
Embodiment 2:
1- oxygen -2,8- diazacyclo nonane derivatives of the present invention are synthesized by following synthetic routes.
Wherein,
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Replace, the unsubstituted furyl of phenyl or unsubstituted thiophene of two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son.
By N- alkenyl α, β-unsaturation nitrone substrate 1 (0.3mmol), isothiocyanate 2 (0.9mmol) are placed in reaction tube In, 3mL toluene is added, 5-20h is stirred to react at 60 DEG C, solvent, silica gel column chromatography on residue is removed under reduced pressure in gained reactant It separates (petroleum ether/methanol=100:1~10:1, volume ratio), obtains target product 3.Different target products and its characterization are such as Under:
3aa: solid, 65mg, 72%yield；mp 96-97℃.1H NMR(400MHz,CDCl3):δ7.54–7.45(m, 2H), 7.41-7.27 (m, 3H), 7.27-7.16 (m, 7H), 7.14-7.05 (m, 2H), 6.76 (d, J=16.0Hz, 1H), 6.28 (d, J=16.0Hz, 1H), 5.11 (d, J=12.5Hz, 1H), 3.45 (dd, J=12.3,1.8Hz, 1H), 3.07 (s, 3H), 2.49 (dd, J=13.0,1.8Hz, 1H), 2.28 (s, 3H), 1.07 (d, J=7.5Hz, 3H)13C NMR(100MHz, CDCl3):δ177.6,157.7,142.2,135.3,135.2,135.0,133.1,130.7,130.5,129.2,129.0, 128.5,128.4,128.2,127.9,126.4,124.5,51.4,45.5,20.7,18.1,15.9；IR(neat):3444, 3033,2926,1724,16451508,976,692cm-1；MS(ESI)m/z[M+H]+calcd for[C29H29N2O2]+: 453.2001；Found:453.2023. its structural formula is as follows:
3ab: solid, 79mg, 58%yield；mp 161-162℃.1H NMR(500MHz,CDCl3):δ7.95–7.87 (m,2H),7.78–7.69(m,4H),7.66–7.57(m,2H),7.56-7.54(m,3H),7.45–7.35(m,2H),7.28- 7.26 (m, 2H), 7.19-7.15 (m, 2H), 6,82 (d, J=16.0Hz, 1H), 6.70 (d, J=16.0Hz, 1H), 6.23 (d, J =10.9Hz, 1H), 4.21 (d, J=10.9Hz, 1H), 3.26 (q, J=7.4Hz, 1H), 2.57 (s, 3H), 1.76 (d, J= 7.4Hz,3H)；13C NMR(125MHz,CDCl3):δ178.5,160.3,139.9,135.7,135.5,134.8,133.7, 132.3,131.9,131.3,131.1,130.9,130.7,130.3,129.7,128.9,128.7,125.1,123.3, 121.3,120.1,49.6,47.4,22.2,15.8.IR(neat):3439,3025,2923,2864,1737,1641,1513, 978,687cm-1；MS(ESI)m/z[M+H]+calcd for[C34H28Br2N2OS]+:671.0367；Found:671.0346. its Structural formula is as follows:
3ac: solid, 32mg, 51%yield；mp 92-93℃.1H NMR(400MHz,CDCl3):δ7.85–7.72(m, 2H), 7.68-7.42 (m, 3H), 5.96-5.80 (m, 1H), 5.38-5.08 (m, 2H), 4.85 (tt, J=12.4,2.0Hz, 1H), 3.87 (dt, J=12.4,2.0Hz, 2H), 2.98 (t, J=13.0Hz, 2H), 2.52-2.46 (m, 2H), 2.23 (q, J= 12.8Hz, 2H), 1.68-1.54 (m, 2H), 0.96 (t, J=13.2Hz, 3H)；13C NMR(100MHz,CDCl3):δ183.7, 162.5,138.1,135.7,134.2,131.5,130.4,129.7,116.7,113.6,49.3,36.3,25.65(s), 25.3,22.2,14.55；IR(neat):3435,3035,2936,2854,1748,1650,969,689cm-1；MS(ESI)m/z [M+H]+calcd for[C18H23N2OS]+:315.1531；Found:315.1562. its structural formula is as follows:
3ad: solid, 86mg, 74%yield；mp 107-108℃.1H NMR(500MHz,CDCl3):δ7.95–7.88 (m,2H),7.73–7.63(m,2H),7.56–7.43(m,8H),7.38–7.21(m,9H),7.02-6.96(m,1H),6.81 (t, J=3.0Hz, 1H), 6.65-6.98 (m, 1H), 5.75 (d, J=12.3Hz, 1H), 4.01 (d, J=12.5Hz, 1H), 3.72(s,3H),1.72(s,3H)；13C NMR(125MHz,CDCl3):δ185.6,164.9,161.5,143.1,141.4, 139.7,1375,135.2,134.8,130.7,129.9,129.8,129.7,128.9,128.8,127.3,126.9,126.7, 126.3,125.6,117.7,114.9,60,59.6,57.3,27.8.IR(neat):3447,3030,2941,2856,1752, 1648,967,698cm-1；MS(ESI)m/z[M+H]+calcd for[C38H33N2O2S]+:581.2263；found: 581.2269. its structural formula is as follows:
3af: solid, 60mg, 60%yield；mp 101-102℃.1H NMR(400MHz,CDCl3):δ7.79–7.70 (m, 2H), 7.63 (d, J=7.5Hz, 2H), 7.59-7.53 (m, 3H), 7.39 (d, J=4.5Hz, 4H), 7.35-7.29 (m, 1H), 7.15 (d, J=7.5Hz, 2H), 5.19 (d, J=6.0Hz, 1H), 3.57 (dd, J=11.9,6.2Hz, 1H), 2.88- 2.82(m,1H),2.53–2.23(m,2H),1.75–1.68(m,2H),1.67–1.57(m,2H),1.56–1.46(m,3H), 1.43–1.34(m,1H)；13C NMR(100MHz,CDCl3):δ185.3,163.1,143.1,142.1,132.3,137.2, 131.09,132.0,130.5,130.2,130.0,129.5,129.4,129.1,128.7,127.2,126.3,124.2, 122.3,53.2,48.3,32.7,29.3,28.9,28.5,27.9.IR(neat):3449,3027,2945,2862,1747, 1654,978,692cm-1；MS(ESI)m/z[M+H]+calcd for[C30H28F3N2OS]+:521.1874；found: 521.1859. its structural formula is as follows:
Experimental example 1: 1- oxygen -2,8- diazacyclo nonane derivatives of the present invention press down a variety of human tumour strains in vitro Activity experiment processed:
(1) cell culture: by T24, HepG2, NCI-H460,7702 cell culture in containing 10% (volume ratio) fetal calf serum With the DMEM culture medium of 1% (volume ratio) dual anti-(containing penicillin and streptomysin), in 37 DEG C of temperature, 5%CO2And 95% air It is cultivated in incubator, changes 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: sample to be tested is added in 96 orifice plates that kind has 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 (8)

1. compound or its pharmaceutically acceptable salt shown in lower formula (I):
Wherein:
R1Indicate phenyl；
R2Indicate phenyl；
R3Indicate phenyl；
R4Indicate phenyl；
R5Indicate methyl；
R6Indicate 3- methoxyphenyl；
X indicates sulphur atom.
2. the synthetic method of compound described in claim 1, it is characterised in that: take compound and formula as shown in following formula (II) (III) compound shown in, is placed in organic solvent, reacts in the presence of oxygen, and object crude product is made；
Wherein:
R1Indicate phenyl；
R2Indicate phenyl；
R3Indicate phenyl；
R4Indicate phenyl；
R5Indicate methyl；
R6Indicate 3- methoxyphenyl；
X indicates sulphur atom.
3. synthetic method according to claim 2, 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.
4. synthetic method according to claim 2, it is characterised in that: reaction carries out under conditions of being lower than 100 DEG C.
5. synthetic method according to claim 2, it is characterised in that: reaction carries out under conditions of being lower than 80 DEG C.
6. the synthetic method according to any one of claim 2~5, it is characterised in that: further include purification step: being specifically Object crude product obtained is subjected to silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization, obtains target after purification Object.
7. synthetic method according to claim 6, it is characterised in that: in silica gel thin-layer chromatography or silica gel column chromatography Eluant, eluent is identical with solvent when recrystallization, and the body of 10:1~1:1 is specially pressed by petroleum ether or n-hexane and ethyl acetate The long-pending mixed solvent than composition, or be made of petroleum ether or methylene chloride and methanol by the volume ratio of 100:1~10:1 Mixed solvent.
8. compound described in claim 1 or its pharmaceutically acceptable salt inhibit lung cancer cell line NCI-H460 or liver in preparation Application in cancer cell line HepG2 drug.
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