CN108727293B - 1,2, 8-oxo diazacyclononane-9-one derivative and synthetic method thereof - Google Patents
1,2, 8-oxo diazacyclononane-9-one derivative and synthetic method thereof Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 3
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- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 238000001308 synthesis method Methods 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
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- 239000012043 crude product Substances 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract 6
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims abstract 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
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- 238000003786 synthesis reaction Methods 0.000 claims description 7
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- 238000001953 recrystallisation Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004809 thin layer chromatography Methods 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
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- 229960001701 chloroform Drugs 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 88
- 229910052739 hydrogen Inorganic materials 0.000 description 35
- 239000001257 hydrogen Substances 0.000 description 35
- 125000005843 halogen group Chemical group 0.000 description 31
- 150000002431 hydrogen Chemical class 0.000 description 29
- 125000001424 substituent group Chemical group 0.000 description 29
- -1 penta-substituted phenyl group Chemical group 0.000 description 28
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
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- 239000007787 solid Substances 0.000 description 22
- 125000004093 cyano group Chemical group *C#N 0.000 description 14
- 125000002541 furyl group Chemical group 0.000 description 14
- 125000001624 naphthyl group Chemical group 0.000 description 14
- 125000000217 alkyl group Chemical group 0.000 description 13
- 125000001544 thienyl group Chemical group 0.000 description 13
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- 239000002253 acid Substances 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- OVGWMLCHHXMCGN-UHFFFAOYSA-N 1,4-diazonan-2-one Chemical class O=C1NCCCCCNC1 OVGWMLCHHXMCGN-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 125000005466 alkylenyl group Chemical group 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical class ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 5
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- 238000012216 screening Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
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- 210000004881 tumor cell Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- SSWVVEYZXQCZNK-UHFFFAOYSA-N 1-isocyano-2-methylpropane Chemical compound CC(C)C[N+]#[C-] SSWVVEYZXQCZNK-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- ZFYAUJTTYSSNEU-UHFFFAOYSA-N diazonane Chemical group C1CCCNNCCC1 ZFYAUJTTYSSNEU-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
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- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- RIWNFZUWWRVGEU-UHFFFAOYSA-N isocyanomethylbenzene Chemical compound [C-]#[N+]CC1=CC=CC=C1 RIWNFZUWWRVGEU-UHFFFAOYSA-N 0.000 description 1
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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Classifications
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 1,2, 8-oxo-diazacyclononane-9-ketone derivative and a synthesis method thereof. The structure of the derivative is shown as the following formula (I), and the synthesis method comprises the following steps: putting a compound shown as a formula (II) and a compound shown as a formula (III) in an organic solvent, and reacting in the presence of oxygen to obtain a target crude product. The method of the invention is simple and easy to control, has short period and does not need anhydrous and anaerobic conditions. The compounds with the structures shown in the formula (I), the formula (II) and the formula (III) are respectively as follows:
R6n ═ C ═ x (iii); wherein: r1Represents 4-nitrophenyl; r2Represents a phenyl group; r3Represents a methyl group; r4Represents a methyl group; r5Represents a hydrogen atom; r6Represents a 4-methylphenyl group; x represents an oxygen atom.
Description
The application is a divisional application of 1-oxygen-2, 8-diazacyclononane derivatives and a synthesis method thereof, and the application dates of the original application are as follows: 2016, 9, 18 days, with application numbers: 201610826407.9, title of the invention: 1-oxo-2, 8-diazacyclononane derivative and its synthesis process.
Technical Field
The invention relates to the technical field of medicines, in particular to a 1-oxygen-2, 8-diazacyclononane derivative and a synthesis method thereof.
Background
The diazacyclononane skeleton is an important core skeleton in natural products and drug molecules, is an important physiological active unit, and has important application in the aspects of tumor resistance, cancer resistance and the like. The use of these compounds has been greatly limited due to the difficulties and challenges in organic synthesis that remain with the diaza nine-membered ring backbone. The current strategy for synthesizing the nine-membered heterocyclic skeleton can be realized by palladium-catalyzed cascade reaction (R.Shintani, K.Ikehata, T.Hayashi, J.Org.Chem.2011,76, 4776-.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a series of 1-oxo-2, 8-diazacyclononane derivatives with novel structures and a synthetic method thereof.
The present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or a halogen atom, or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thia-l groupThienyl, or unsubstituted naphthyl; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R5represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R6represents hydrogen, C1～12Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-or tetra-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
x represents an oxygen or sulfur atom.
Among the above compounds:
R1further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R2further preferably hydrogen or C1～4An alkyl group, a carboxyl group,or is unsubstituted, mono-or di-substituted phenyl;
R3further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R4further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R5further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R6further preferably hydrogen or C1～12Alkyl, or phenyl which is unsubstituted, mono-or di-substituted.
The synthesis method of the compound shown in the formula (I) mainly comprises the following steps: taking a compound shown as a formula (II) and a compound shown as a formula (III), placing the compounds in an organic solvent, and reacting in the presence of oxygen to obtain a target crude product;
wherein:
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy of (2)Base, C1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R5represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R6represents hydrogen, C1～12Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-or tetra-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
x represents an oxygen or sulfur atom.
In the above synthesis method, R1、R2、R3、R4、R5And R6The preferences of (2) are as previously described.
In the above synthesis method, the compound represented by formula (II) is an N-alkenyl α, β -unsaturated nitrone derivative, which can be synthesized by referring to the 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), or can be synthesized by optionally designing a synthesis route, and will not be described in detail herein. The compound of formula (III) is isonitrile acid ester or isonitrile acid ester, and can be directly obtained from the market (such as phenyl isonitrile acid, isobutyl isonitrile acid ester, benzyl isonitrile acid ester, phenyl isonitrile acid ester, etc.)
In the above synthesis method, the organic solvent may be one or a combination of two or more selected from benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane and dioxane. When the organic solvent is selected from the combination of two or more of the above substances, the ratio of the organic solvent to the organic solvent may be any ratio.
In the above synthesis method, the reaction is carried out under air conditions, and preferably at a temperature of less than 100 ℃, more preferably at a temperature of from room temperature to 80 ℃, and even more preferably at a temperature of 80 ℃. The completion of the reaction can be followed by TLC. According to the experience of the applicant, when the reaction is carried out at the temperature of between normal temperature and 80 ℃, the reaction time is preferably controlled to be between 5 and 20 hours.
In the synthesis method of the present invention, the amount ratio of the raw materials is stoichiometric, and in actual operation, the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is usually 1.0: 1.0 to 5.0. The amount of the organic solvent is preferably such that the raw materials participating in the reaction can be dissolved, and in general, all the raw materials participating in the reaction are dissolved in 1 to 10mL of the organic solvent based on 1mmol of the compound represented by the formula (II).
The crude compound of formula (I) is obtained by the above process and can be purified by conventional purification methods to increase the purity of the compound of formula (I). The purification is usually carried out by silica gel thin layer chromatography or silica gel column chromatography, or by recrystallization, using the same eluent as used for the chromatography and the same solvent as used for the recrystallization, and using petroleum ether and ethyl acetate in a ratio of 10: 1-1: 1, or a mixed solvent composed of n-hexane and ethyl acetate in a volume ratio of 10: 1-1: 1, or a mixed solvent composed of petroleum ether and methanol in a volume ratio of 100: 1-10: 1, or a mixed solvent composed of dichloromethane and methanol in a volume ratio of 100: 1-10: 1.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Compared with the prior art, the invention provides a series of 1-oxo-2, 8-diazacyclononane derivatives with novel structures and a synthesis method thereof.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
The N-alkenyl α, β -unsaturated nitrone derivatives (i.e., compounds represented by formula (II)) referred to in the following examples were synthesized according to the following synthetic routes:
wherein,
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or a perfluoroalkyl or halogen atom, or an unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, orAn unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R5represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl group or halogen atom of (2).
General formula (Cu), (OAc)2(0.3mmol,54mg), α, β -unsaturated oxime substrate S1(0.3mmol) and alkenylboronic acid S2(0.9mmol) were placed in a reaction tube, 3mL of 1, 2-dichloroethane were added, and pyridine (3mmol,0.24mL) was added at room temperature; stirring at 25 ℃ for 12-24 h, adding water (10mL) into the obtained reaction product, extracting with dichloromethane (2 × 10mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing the solvent under reduced pressure, and separating the residue by silica gel column chromatography (petroleum ether/ethyl acetate is 10: 1-1: 1 in volume ratio) to obtain the target product 1 (namely the compound N-alkenyl alpha, beta-unsaturated nitrone shown in the formula (II)).
The isonitrile esters and isothionitrile esters (i.e., the compounds represented by the formula (III)) mentioned in the following examples were all obtained directly from the market.
Example 1
The 1-oxo-2, 8-diazacyclononane derivatives of the present invention were synthesized according to the following synthetic route.
Wherein,
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R5represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R6represents hydrogen, C1～12Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-or tetra-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4Alkyl group, cyano group or halogen atom.
Putting an N-alkenyl alpha, beta-unsaturated nitrone substrate 1(0.3mmol) and an isonitrile ester 2(0.9mmol) into a reaction tube, adding 3mL of dimethyl sulfoxide, stirring at 80 ℃ for reaction for 5-20h, adding water (10mL) into the obtained reaction product, extracting with dichloromethane (2X 10mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing the solvent under reduced pressure, and separating the residue by silica gel column chromatography (petroleum ether/ethyl acetate is 10: 1-1: 1 in volume ratio) to obtain a target product 3. The different target products and their characterization were as follows:
solid, 66mg, 76% yield 3 a; mp 100-.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; 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; 497.2470, its structural formula is as follows:
3c solid, 67mg, 59% yield; mp 98-99 ℃.1H NMR(400MHz,CDCl3):δ7.60(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):δ178.3,155.2,148.6,140.1,138.9,137.2,136.2,130.5,129.9,129.5,127.8,127.4,126.9,126.8(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; 573.1963, its structural formula is as follows:
solid, 72.5mg, 61% yield 3 d; mp 153-.1H NMR(500MHz,CDCl3):δ7.42(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):δ178.7,155.6,144.1,138.9,137.5,136.3,135.9,133.1,132.2,130.8,130.1,129.3,128.9,128.5,126.4,124.7,122.3,121.7,48.2,45.7,21.8,21.6,14.6.IR(neat):3433,3022,2919,2858,1722,1632,1486,974,658cm-1；MS(ESI)m/z[M+H]+calcd for[C28H27Br2N2O2]+593.0439; 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):δ156.2,152.3,138.4,136.8,136.0,134.8,132.3,130.5,130.3,130.2,125.5,122.6,36.7,33.6,22.4,19.9,18.8.IR(neat):3426,3014,2927,2846,1713,1647,1467,989,654cm-1；MS(ESI)m/z[M+H]+calcd for[C21H23N2O2]+335.1760; 335.1743, its structural formula is as follows:
3f solids, 51mg, 56% yield; mp 165-166 ℃.1H NMR(400MHz,CDCl3):δ8.21(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; 456.1919, its structural formula is as follows:
3g of 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; 349.1925, its structural formula is as follows:
solid, 37mg, 46% yield 3 h; 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; 403.1654, its structural formula is as follows:
3i solid, 63mg, 63% yield; mp 104-.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; 499.2364, its structural formula is as follows:
3j solid, 54mg, 58% yield; mp 103 and 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; 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):δ180.8,156.0,143.4,139.7,137.1,136.8,135.5,131.4,129.7,129.4,128.9,128.7,128.0,127.7,127.4,126.7,125.2,123.9,55.1,44.8,35.8,30.9,30.2,26.9,21.1.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; 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; 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).13CNMR(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; 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; 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):δ178.53(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; 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; 451.2368, its structural formula is as follows:
3q solids, 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; 451.2391, its structural formula is as follows:
example 2:
the 1-oxo-2, 8-diazacyclononane derivatives of the present invention were synthesized according to the following synthetic route.
Wherein,
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group,or is unsubstituted naphthyl; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R5represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R6represents hydrogen, C1～12Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-or tetra-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4Alkyl group, cyano group or halogen atom.
Putting an N-alkenyl alpha, beta-unsaturated nitrone substrate 1(0.3mmol) and isothiocyanato 2(0.9mmol) into a reaction tube, adding 3mL of toluene, stirring at 60 ℃ for reaction for 5-20h, removing the solvent from the obtained reaction product under reduced pressure, and separating the residue by silica gel column chromatography (petroleum ether/methanol is 100: 1-10: 1, volume ratio) to obtain a target product 3. The different target products and their characterization were as follows:
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; 453.2023, its structural formula is as follows:
3ab solid, 79mg, 58% yield; mp 161 and 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; 671.0346, its structural formula is as follows:
3ac solids, 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; 315.1562, its structural formula is as follows:
3ad, solids, 86mg, 74% yield; mp 107-.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; 581.2269, its structural formula is as follows:
3af solid, 60mg, 60% yield; mp 101-.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; 521.1859, its structural formula is as follows:
experimental example 1: the 1-oxygen-2, 8-diazacyclononane derivative provided by the invention is used for carrying out in-vitro inhibitory activity experiments on various human tumor strains:
(1) cell culture: t24, HepG2, NCI-H460, 7702 cells were cultured in DMEM medium containing 10% (by volume) fetal bovine serum and 1% (by volume) diabody (containing penicillin and streptomycin) at 37 ℃ with 5% CO2And culturing in 95% air incubator, and changing culture medium every other day. And (5) carrying out passage after the cells grow full, and freezing and storing.
(2) Plate preparation: taking the cells in logarithmic growth phase, removing the old culture medium, washing twice by PBS, digesting the cells by trypsin, adding a new culture medium after the cells become round to stop cell digestion and blowing suspension cells to prepare single cell suspension. Taking a proper amount of cell suspension, adding a certain amount of culture medium for dilution, and inoculating the cell suspension into a 96-well plate, wherein each well contains 180 mu L of cells, and the number of the cells in each well is 20000-40000.
(3) Adding medicine: the sample to be tested was added to a 96-well plate seeded with tumor cells at 20. mu.L per well to give a final concentration of 10. mu.M, and primary screening was performed. And (4) setting different concentration gradients for the compounds according to the result of primary screening, and setting 5 compound holes in each group. Adding compound and then releasing CO2Culturing in incubator for 48 hr, adding 10 μ L of prepared MTT solution into each well, and discharging CO2And continuously culturing for 4-6 h in the incubator.
(4) And (3) testing: removing the culture medium in the 96-well plate by suction, adding 100 mu L DMSO, placing on a shaking table, shaking for 5-10 min,crystallized formazan was completely dissolved. The absorbance (OD) was measured at an absorption wavelength of 570nm and a reference wavelength of 630nm using a microplate reader, and the inhibition ratio was calculated. Inhibition rate (1-sample group OD value/blank group OD value) × 100%, and IC of each compound for different tumor cell lines was calculated by SPSS software50The value is obtained. The test results are shown in table 1 below:
table 1:
Claims (8)
1. a compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1represents 4-nitrophenyl;
R2represents a phenyl group;
R3represents a methyl group;
R4represents a methyl group;
R5represents a hydrogen atom;
R6represents a 4-methylphenyl group;
x represents an oxygen atom.
2. A method of synthesizing the compound of claim 1, wherein: taking a compound shown as a formula (II) and a compound shown as a formula (III), placing the compounds in an organic solvent, and reacting in the presence of oxygen to obtain a target crude product;
wherein:
R1represents 4-nitrophenyl;
R2represents a phenyl group;
R3represents a methyl group;
R4represents a methyl group;
R5represents a hydrogen atom;
R6represents a 4-methylphenyl group;
x represents an oxygen atom.
3. The method of synthesis according to claim 2, characterized in that: the organic solvent is one or more of benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, trichloromethane, n-hexane and dioxane.
4. The method of synthesis according to claim 2, characterized in that: the reaction is carried out at a temperature below 100 ℃.
5. The method of synthesis according to claim 2, characterized in that: the reaction is carried out at a temperature below 80 ℃.
6. The synthesis method according to any one of claims 2 to 5, wherein: further comprises a purification step: specifically, the prepared crude target product is subjected to silica gel thin layer chromatography or silica gel column chromatography, or recrystallization to obtain the purified target product.
7. The method of synthesis according to claim 6, characterized in that: the eluent used in silica gel thin layer chromatography or silica gel column chromatography is the same as the solvent used in recrystallization, and the eluent is prepared from petroleum ether and ethyl acetate according to the weight ratio of 10: 1-1: 1, or a mixed solvent composed of n-hexane and ethyl acetate in a volume ratio of 10: 1-1: 1, or a mixed solvent composed of petroleum ether and methanol in a volume ratio of 100: 1-10: 1, or a mixed solvent composed of dichloromethane and methanol in a volume ratio of 100: 1-10: 1.
8. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-neoplastic drug.
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| US3152145A (en) * | 1962-05-23 | 1964-10-06 | American Home Prod | 5-aryl-3, 1, 4-benzoxadiazepine-2 (1h)-ones |
| CN101395143A (en) * | 2005-12-29 | 2009-03-25 | 安姆弗拉玛法国股份公司 | Aza heterocyclics for the treatment of malaria or aids |
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| CN101395143A (en) * | 2005-12-29 | 2009-03-25 | 安姆弗拉玛法国股份公司 | Aza heterocyclics for the treatment of malaria or aids |
| CN105601582A (en) * | 2016-01-26 | 2016-05-25 | 兰州大学 | Compound extracted from elymus dahuricus and preparation method and application thereof |
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