CN111018885A - 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof - Google Patents

1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof Download PDF

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CN111018885A
CN111018885A CN201911264858.8A CN201911264858A CN111018885A CN 111018885 A CN111018885 A CN 111018885A CN 201911264858 A CN201911264858 A CN 201911264858A CN 111018885 A CN111018885 A CN 111018885A
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莫冬亮
马小盼
农彩梅
徐佩佩
苏桂发
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Changzhou Chuangwo New Materials Technology Co ltd
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Abstract

The invention discloses a series of 1, 2-dioxy cyclohexene [3,4-f]Nitrogen oxo cyclononane derivative and its synthesis process and application. The 1, 2-dioxycyclohexene [3,4-f ] of the invention]The nitrogen oxo-cyclononane derivative has a structure shown as the following formula (I), and the synthesis method mainly comprises the following steps: placing a compound shown as a formula (II), a compound shown as a formula (III), a photosensitizer and a catalyst in an organic solvent, and reacting under light irradiation in the presence of oxygen to obtain a crude product of a target compound. The method is simple and easy to control, and the obtained partial target compounds have good anti-inflammatory activity and certain potential medicinal value. The compounds with the structures shown in the formula (I), the formula (II) and the formula (III) are respectively as follows:

Description

1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof
Technical Field
The invention relates to a 1, 2-dioxirane [3,4-f ] nitrogen oxo cyclononane derivative, a synthetic method and application thereof, belonging to the technical field of medicines.
Background
Organic peroxides are compounds formed by peroxide bonds to carbon atoms. The greatest effect of these compounds has long been as free radical initiators. Until the 70's of the 20 th century, scientists in China discovered a natural product artemisinin with excellent antimalarial activity, in which the peroxy bond in the molecule was the key to its antimalarial activity. Organic peroxides are beginning to be highly appreciated by the medical and biological communities and are gradually drawing new interests in the chemical community. The key steps and difficulties in the synthesis of such peroxy compounds are how the peroxy linkage is formed or introduced. Organic peroxides of natural origin are of limited variety and the amount of each compound that can be isolated is usually very small. It is important to develop an efficient method for synthesizing various organic peroxides. However, 1, 2-dioxirane [3,4-f ] nitrogen-oxygen cyclononane derivatives are not reported at present, so that the research on the synthesis and the application of the derivatives is of great significance for finding new lead compounds.
Disclosure of Invention
The invention aims to provide a series of 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivatives with novel structures, and a synthetic method and application thereof.
The 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative is a compound shown as the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0002312540640000011
wherein:
R1represents a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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, cyano or halogen ofAn atom;
R2represents a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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;
R3is represented by 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 a hydrogen atom, 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);
R5is represented by 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).
Among the above compounds:
R1further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R2further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R3further preferred is 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;
R5more preferably C1～4Alkyl, 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: placing a compound shown as a formula (II), a compound shown as a formula (III), a photosensitizer and a catalyst in an organic solvent, and reacting under the irradiation of lamplight in the presence of oxygen to obtain a crude product of a target compound;
Figure BDA0002312540640000021
wherein:
R1represents a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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 a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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;
R3is represented by 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、C1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents a hydrogen atom, 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);
R5is represented by 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);
the catalyst is one or the combination of more than two of copper salt, ytterbium salt and scandium salt.
In the above synthesis method, R1、R2、R3、R4And R5The preferences of (2) are as previously described.
In the above-mentioned synthesis method, the compound represented by the formula (II) is N-alkenyl α -unsaturated nitrone derivative, which can be synthesized by referring to the existing literature (Xiao-Pan Ma, Liang-Gui Li, Hong-Ping ZHao, Min Du, Cui Liang, and an and Dong-Liang Mo. org. Lett.2018,20,4571-4574.) or by optionally designing a synthesis route, which is not described in detail herein, and the compound represented by the formula (III) is a methylene cyclopropane derivative, which can be synthesized by referring to the existing literature (Xiao-Pan Ma, Jie-FeZHu, Si-Yi Wu, Chun-Hua N, Ning Zou, Cui Liang, Gui-FaSu, and Dong-Liang Mo. J. Org.7, 82, 502. the synthesis route can be also not described herein.
In the above synthesis method, the photosensitizer may be eosin y (eosin y).
In the above synthesis method, the presence of the catalyst determines whether the target compound is produced, and the production of the target compound is accelerated. The copper salt in the catalyst is preferably one or the combination of more than two of copper bromide, copper iodide, copper chloride, copper sulfate, acetic acid ketone, copper trifluoromethanesulfonate, cuprous bromide, cuprous iodide and cuprous chloride; the ytterbium salt is preferably ytterbium trifluoromethanesulfonate; the scandium salt is preferably scandium trifluoromethanesulfonate. The catalyst is generally used in an amount of 0.1 to 0.5 times the amount of the compound material represented by the formula (II).
In the synthesis method, the reaction is carried out under the irradiation of a white light LED lamp. The power of the white light LED can be selected according to the requirement, and can be 2-14W generally.
In the above synthesis method, the organic solvent is one or a combination of two or more selected from toluene, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, tert-butyl methyl ether (TBME), dichloromethane, acetone, chloroform 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. 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).
In the above synthesis method, the reaction is generally carried out under air conditions. The reaction may be carried out with or without heating, preferably at a temperature of less than 80 ℃ and further at a temperature of less than 60 ℃, more preferably at a temperature of from room temperature to 40 ℃. The completion of the reaction can be followed by TLC. According to the experience of the applicant, when the reaction is carried out under the normal temperature condition, the reaction time is preferably controlled to be 2-10 days.
In the synthesis method of the invention, the amount and the ratio of the raw materials are stoichiometric, and in actual operation, the molar ratio of the compound represented by the formula (II), the compound represented by the formula (III) and the photosensitizer is usually 1.0: 1.0-2.0: 0.1 to 0.5.
The crude compound of formula (I) obtained by the above process may be purified by conventional purification methods to increase the purity of the compound of formula (I), and therefore, the process of the present invention preferably further comprises a step of purifying the crude compound of interest. The purification step is to purify the crude product of the compound shown in the formula (I) by adopting silica gel column chromatography or recrystallization, wherein an eluant used in chromatography is the same as a solvent used in recrystallization, and the eluant is a mixed solvent composed of petroleum ether and ethyl acetate, or a mixed solvent composed of n-hexane and ethyl acetate. In the mixed solvent, the volume ratio of the petroleum ether to the ethyl acetate is preferably 30: 1-10: 1, and the volume ratio of the n-hexane to the ethyl acetate is preferably 30: 1-10: 1.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof in preparing a medicament for treating inflammation.
The invention further comprises a pharmaceutical composition which contains a therapeutically effective dose of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
Compared with the prior art, the invention provides a series of 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivatives with novel structures, and the synthetic methods are simple and easy to control; the test result of the applicant shows that the obtained partial target compounds have better anti-inflammatory activity and certain potential medicinal value.
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.
Example 1
The 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxide cyclononane derivative provided by the invention is synthesized according to the following synthetic route.
Figure BDA0002312540640000041
3aa:R1＝Ph,R2＝Ph,R3＝Me,R4＝Me,R5＝cinnamyl；
3ba:R1＝4-OMeC6H4,R2＝4-OMeC6H4,R3＝Me,R4＝Me,R5＝cinnamyl；
3ca:R1＝4-CF3C6H4,R2＝4-OMeC6H4,R3＝Me,R4＝Me,R5＝cinnamyl；
3da:R1＝3-BrC6H4,R2＝3-BrC6H4,R3＝Me,R4＝Me,R5＝styryl；
3ea:R1＝2-BrC6H4,R2＝2-BrC6H4,R3＝Me,R4＝Me,R5＝cinnamyl；
3fa:R1＝2-thienyl,R2＝2-thienyl,R3＝Me,R4＝Me,R5＝cinnamyl；
3ga:R1＝Ph,R2＝Ph,R3＝Et,R4＝Et,R5＝cinnamyl；
3ha:R1＝Ph,R2＝Ph,R3＝Ph,R4＝Et,R5＝cinnamyl；
3ia:R1＝Ph,R2＝Ph,R3＝-CH2-,R4＝-(CH2)2-,R5＝cinnamyl；
3ja:R1＝Ph,R2＝Ph,R3＝-CH2-,R4＝-(CH2)3-,R5＝cinnamyl；
3ka:R1＝Ph,R2＝Ph,R3＝-CH2-,R4＝-(CH2)4-,R5＝cinnamyl。
To a dry glass vial equipped with a stir bar was added the corresponding N-alkenyl α -unsaturated nitrone 1(0.2mmol), ytterbium triflate (Yb (OTf)320 mol%, 0.04mmol), Eosin Y (Eosin Y, 20 mol%) and 2mL of an organic solvent (wherein TBME is used as the organic solvent for the target compounds 3aa to 3ea, toluene, tetrahydrofuran, ethyl acetate, acetonitrile and diethyl ether are used as the organic solvent for the target compounds 3fa to 3ja, and toluene, tetrahydrofuran, ethyl acetate, acetonitrile and diethyl ether are used as the organic solvent for the target compound 3 ka)Methylene cyclopropane 2(0.4mmol) was added to the vial, the vial was sealed with a preservative film, then the vial containing the mixture was stirred at room temperature and allowed to react under illumination by a white LED lamp (14W) for 3-7 days until complete consumption of the N-alkenyl α -unsaturated nitrone 1 (monitored by TLC), at which time the resulting reaction was freed of solvent under reduced pressure and the residue was chromatographed on silica gel column (30: 1-10: 1, volume ratio petroleum ether/ethyl acetate) to give target product 3. different target products and their characterization were as follows:
3 aa: pale yellow solid, 93mg, 85% yield; mp 166-167 deg.C;1H NMR(400MHz,CDCl3):δ7.29(d,J＝7.2Hz,2H),7.19–7.09(m,11H),6.93(d,J＝6.8Hz,2H),6.56(d,J＝15.6Hz,1H),6.12(dt,J＝15.6Hz,6.8Hz,1H),5.80–5.76(m,1H),5.62–5.58(m,1H),5.46–5.42(m,1H),4.70–4.58(m,2H),3.95(s,1H),3.29–3.28(m,1H),2.69–2.64(m,1H),1.87(s,3H),1.44(d,J＝7.2Hz,3H),1.19–1.18(m,1H),1.12–1.07(m,1H),1.01–0.96(m,1H),0.80–0.73(m,1H)；13C NMR(100MHz,CDCl3):δ172.4,169.4,142.8,136.4,135.8,135.4,135.3,129.3,128.5,128.4,128.2,128.1,127.9,127.8,126.6,126.4,124.9,122.2,79.8,77.5,65.4,62.8,50.8,49.4,46.0,21.7,12.4,11.2,9.3；IR(thin film)3022,2964,1737,1641,1450,1148,1001,695cm-1；HRMS(ESI)m/z calcd for C35H36NO5[M+H]+550.2593 and found 550.2618, the structural formula is as follows:
Figure BDA0002312540640000051
3 ba: pale yellow solid, 96mg, 79% yield; mp 150-151 deg.C;1H NMR(400MHz,CDCl3):δ7.27–7.25(m,7H),6.98(d,J＝8.4Hz,2H),6.80(d,J＝8.0Hz,2H),6.72(d,J＝8.4Hz,2H),6.64(d,J＝16.0Hz,1H),6.21–6.14(m,1H),5.80–5.76(m,1H),5.70–5.62(m,1H),5.50–5.41(m,1H),4.80–4.64(m,2H),4.01(s,1H),3.72(s,6H),3.34–3.29(m,1H),2.77–2.72(m,1H),1.94(s,3H),1.47(d,J＝7.2Hz,3H),1.29–1.25(m,1H),1.18–1.13(m,1H),1.08–1.04(m,1H),0.87–0.81(m,1H)；13C NMR(100MHz,CDCl3):δ172.6,169.5,159.8,158.0,135.8,135.6,135.3,135.0,130.2,129.6,128.5,128.3,128.1,126.5,125.1,122.2,113.6,113.2,79.4,77.6,65.4,62.8,55.1,55.0,50.1,49.4,46.0,21.7,12.4,11.3,9.4；IR(thinfilm)3003,2938,1739,1610,1512,1147,1028,694cm-1；HRMS(ESI)m/z calcd forC37H40NO7[M+H]+610.2799 and found 610.2794, the structural formula is as follows:
Figure BDA0002312540640000052
3 ca: pale yellow solid, 110mg, 80% yield; mp 163-164 deg.C;1H NMR(400MHz,CDCl3):δ7.52(d,J＝8.0Hz,2H),7.44(d,J＝7.6Hz,2H),7.39(d,J＝8.0Hz,2H),7.31–7.25(m,5H),7.02(d,J＝8.0Hz,2H),6.66(d,J＝16.0Hz,1H),6.23–6.16(m,1H),5.90–5.85(m,1H),5.71–5.67(m,1H),5.58–5.50(m,1H),4.81–4.66(m,2H),4.02(s,1H),3.39–3.38(m,1H),2.65–2.60(m,1H),1.97(s,3H),1.52(d,J＝7.2Hz,3H),1.31–1.17(m,2H),1.10–1.04(m,1H),0.87–0.82(m,1H)；13C NMR(100MHz,CDCl3):δ171.6,169.2,146.7,140.3,136.1,135.8,135.7,131.2(q,J＝32.0Hz),129.5,129.0(q,J＝45.2Hz),128.6,128.4,127.6,126.5,125.5(d,J＝36.4Hz),125.3(q,J＝3.6Hz),124.9(q,J＝3.6Hz),124.0,122.8(d,J＝36.4Hz),121.9,78.8,77.3,65.6,62.9,50.4,49.3,45.9,21.7,12.1,11.1,9.3；19F NMR(100MHz,CDCl3):δ-62.4,-62.6；IR(thin film)3023,2966,1732,1617,1325,1122,692cm-1；HRMS(ESI)m/z calcd for C37H34F6NO5[M+H]+686.2336 and found 686.2331, the structural formula is as follows:
Figure BDA0002312540640000061
3 da: pale yellow solid, 106mg, 75% yield; mp is 75-76 deg.C;1H NMR(400MHz,CDCl3):δ7.40(s,1H),7.27–7.18(m,8H),7.12(t,J＝7.6Hz,1H),7.03(s,1H),6.99(t,J＝7.6Hz,1H),6.85(d,J＝7.6Hz,1H),6.58(d,J＝16.0Hz,1H),6.15–6.07(m,1H),5.80–5.71(m,1H),5.58–5.53(m,1H),5.37–5.32(m,1H),4.73–4.59(m,2H),3.93(s,1H),3.20–3.18(m,1H),2.61–2.56(m,1H),1.90(s,3H),1.46(d,J＝7.2Hz,3H),1.18–1.10(m,2H),0.99–0.98(m,1H),0.80–0.75(m,1H)；13C NMR(100MHz,CDCl3):δ171.9,169.2,144.9,138.5,135.7,135.6,132.2,131.7,130.6,130.0,129.6,129.5,128.6,128.2,127.7,126.5,126.4,126.3,124.1,122.3,122.0,121.9,78.9,77.1,65.6,62.8,50.0,49.1,46.2,21.8,12.2,11.1,9.2；IR(thin film)3021,2963,1734,1594,1261,1023,803cm-1；HRMS(ESI)m/z calcdfor C35H34Br2NO5[M+H]+706.0798 and found 706.0799, the structural formula is as follows:
Figure BDA0002312540640000062
3 ea: pale yellow solid, 73mg, 52% yield; mp: 181-182 ℃;1H NMR(400MHz,CDCl3):δ7.52(d,J＝7.6Hz,1H),7.46(d,J＝8.0Hz,1H),7.30(d,J＝7.2Hz,1H),7.20–7.18(m,6H),7.01–6.91(m,4H),6.55(d,J＝16.0Hz,1H),6.11–6.04(m,1H),5.90–5.85(m,1H),5.83–5.76(m,1H),5.64–5.57(m,1H),4.72–4.57(m,2H),4.15–4.09(m,2H),2.44–2.39(m,1H),1.96(s,3H),1.46(d,J＝7.2Hz,3H),1.26–1.11(m,2H),0.98–0.94(m,1H),0.82–0.78(m,1H)；13CNMR(100MHz,CDCl3):δ171.8,169.2,142.2,135.9,135.6,134.9,132.5,132.1,131.0,129.7,129.4,128.5,128.4,128.0,127.9,127.1,127.0,126.5,126.4,124.7,123.4,122.2,78.3,76.8,65.2,62.9,49.0,46.5,46.3,21.8,11.7,11.1,9.4；IR(thin film)3024,2945,1730,1466,1162,1025,747cm-1；HRMS(ESI)m/z calcd for C35H34Br2NO5[M+H]+706.0798 and found 706.0797, the structural formula is as follows:
Figure BDA0002312540640000071
3 fa: pale yellow solid, 64mg, 57% yield; mp 151-152 deg.C;1H NMR(400MHz,CDCl3):δ7.21–7.17(m,5H),7.10–7.04(m,2H),6.90–6.75(m,4H),6.59(d,J＝16.0Hz,1H),6.17–6.10(m,1H),5.72–5.70(m,3H),4.76–4.58(m,2H),3.92(s,1H),3.70–3.69(m,1H),2.73–2.68(m,1H),1.89(s,3H),1.42(d,J＝7.2Hz,3H),1.21–1.16(m,1H),1.12–1.06(m,1H),0.98–0.93(m,1H),0.80–0.74(m,1H)；13C NMR(100MHz,CDCl3):δ171.7,169.1,143.8,138.3,135.8,135.5,135.4,128.5,128.1,127.9,126.7,126.6,126.4,126.0,125.9,124.5,123.7,122.2,77.6,74.6,65.5,62.7,48.9,46.4,46.0,21.8,12.3,11.3,9.4；IR(thin film)3010,2962,1738,1640,1445,1147,1027,692cm-1；HRMS(ESI)m/z calcd for C31H32S2NO5[M+H]+562.1716 and found 562.1716, the structural formula is as follows:
Figure BDA0002312540640000072
3 ga: pale yellow solid, 76mg, 66% yield; mp 121-122 deg.C;1H NMR(400MHz,CDCl3):δ7.30–7.25(m,2H),7.21–7.15(m,7H),7.11–7.04(m,4H),6.88(d,J＝7.2Hz,2H),6.55(d,J＝16.0Hz,1H),6.11(dt,J＝15.6Hz,6.8Hz,1H),5.80–5.76(m,1H),5.60–5.53(m,1H),5.40–5.35(m,1H),4.70–4.56(m,2H),4.01(s,1H),3.15–3.14(m,1H),2.41–2.28(m,3H),2.14–1.99(m,2H),1.22–1.16(m,2H),1.10(t,J＝7.2Hz,3H),0.97–0.91(m,1H),0.87(t,J＝7.2Hz,3H),0.80–0.73(m,1H)；13C NMR(100MHz,CDCl3):δ175.1,169.3,142.9,136.5,135.8,135.4,135.3,129.3,128.5,128.4,128.2,128.1,127.9,127.8,126.5,126.4,124.3,122.2,79.6,77.5,65.4,62.6,53.4,51.2,48.6,30.8,20.8,13.2,11.2,11.1,9.3；IR(thin film)3028,2970,1737,1599,1453,1154,1023,698cm-1；HRMS(ESI)m/z calcd forC37H40NO5[M+H]+578.2901 and found 578.2901, the structural formula is as follows:
Figure BDA0002312540640000081
3 ha: light yellowColor solid, 84mg, 67% yield; mp 169-170 deg.C;1H NMR(400MHz,CDCl3):δ7.44(d,J＝7.2Hz,2H),7.35–7.34(m,2H),7.26–7.01(m,14H),6.86(d,J＝6.8Hz,2H),6.50(d,J＝16.0Hz,1H),6.04–5.97(m,1H),5.90–5.86(m,1H),5.58–5.54(m,1H),5.39–5.35(m,1H),4.65–4.50(m,2H),4.09(s,1H),3.42–3.41(m,1H),3.09–3.06(m,1H),2.48–2.40(m,1H),2.14–2.09(m,1H),1.28–1.17(m,2H),1.04–1.01(m,1H),0.82–0.81(m,1H),0.78(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ172.0,169.2,142.9,136.7,136.4,135.7,135.3,129.8,129.3,128.6,128.5,128.4,128.2,128.1,128.0,127.8,126.9,126.5,126.4,126.3,124.5,122.0,79.5,77.6,65.3,63.4,53.6,51.6,49.1,21.3,13.4,11.1,9.3；IR(thin film)3027,2951,1735,1493,1155,966,694cm-1；HRMS(ESI)m/z calcd forC41H40NO5[M+H]+626.2901 and found 626.2899, the structural formula is as follows:
Figure BDA0002312540640000082
3 ia: pale yellow oil, 54mg, 48% yield;1H NMR(400MHz,CDCl3):δ7.36–7.24(m,14H),7.16(d,J＝7.2Hz,1H),6.71(d,J＝15.6Hz,1H),6.32–6.23(m,1H),5.96–5.84(m,1H),5.68–5.65(m,1H),5.63–5.60(m,1H),4.81(d,J＝6.4Hz,2H),3.77–3.73(m,1H),3.54(s,1H),3.46–3.41(m,1H),2.29–2.24(m,1H),1.98–1.60(m,4H),1.35–1.14(m,4H),0.76–0.71(m,1H)；13C NMR(100MHz,CDCl3):δ179.8,170.6,141.1,136.3,136.0,135.9,134.7,129.7,129.0,128.7,128.5,128.4,128.3,128.1,127.9,126.5,126.4,122.5,82.3,81.0,65.5,64.3,56.2,54.6,45.7,32.6,31.0,28.3,10.7,9.5；IR(thin film)3023,2950,1725,1449,1225,1023,695cm-1；HRMS(ESI)m/z calcd for C36H36NO5[M+H]+562.2588 and found 562.2573, the structural formula is as follows:
Figure BDA0002312540640000083
3ja：pale yellow oil, 37mg, 32% yield;1H NMR(400MHz,CDCl3):δ7.35–7.24(m,14H),7.17(d,J＝7.2Hz,1H),6.70(d,J＝15.6Hz,1H),6.31–6.23(m,1H),5.95–5.85(m,1H),5.68–5.66(m,1H),5.64–5.61(m,1H),4.81(d,J＝6.4Hz,2H),3.75–3.74(m,1H),3.53(s,1H),3.45–3.42(m,1H),2.28–2.23(m,1H),1.99–1.61(m,5H),1.34–1.13(m,5H),0.75–0.70(m,1H)；13C NMR(100MHz,CDCl3):δ179.8,170.5,141.0,136.2,136.0,135.8,134.7,129.6,129.1,128.6,128.5,128.4,128.2,128.1,127.9,126.6,126.4,122.6,82.1,81.0,65.4,64.3,56.0,54.5,45.8,32.7,31.1,28.7,28.0,10.8,9.4；IR(thin film)3022,2949,1729,1449,1226,1023,694cm-1；HRMS(ESI)m/z calcd for C37H38NO5[M+H]+576.2744 and found 576.2732, the structural formula is as follows:
Figure BDA0002312540640000091
3 ka: pale yellow solid, 53mg, 45% yield; mp 113-114 deg.C;1H NMR(400MHz,CDCl3):δ7.36–7.22(m,14H),7.19(d,J＝7.2Hz,1H),6.71(d,J＝15.6Hz,1H),6.30–6.23(m,1H),5.95–5.88(m,1H),5.69–5.67(m,1H),5.65–5.63(m,1H),4.82(d,J＝6.4Hz,2H),3.76–3.74(m,1H),3.53(s,1H),3.45–3.43(m,1H),2.29–2.26(m,1H),1.98–1.60(m,7H),1.35–1.14(m,5H),0.74–0.71(m,1H)；13C NMR(100MHz,CDCl3):δ179.9,170.5,141.1,136.1,136.0,135.9,134.5,129.7,129.1,128.6,128.5,128.4,128.2,128.0,127.9,126.6,126.5,122.6,82.2,81.0,65.5,64.1,56.1,54.6,45.8,32.8,31.1,29.6,28.7,28.1,10.9,9.3；IR(thin film)3028,2930,1733,1494,1148,1022,696cm-1；HRMS(ESI)m/z calcd forC38H40NO5[M+H]+590.2901 and found 590.2901, the structural formula is as follows:
Figure BDA0002312540640000092
comparative example 1
Example 1 was repeated except that: ytterbium triflate was not added prior to the reaction.
As a result, the objective product was not obtained.
Example 2
The 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxide cyclononane derivative provided by the invention is synthesized according to the following synthetic route.
Figure BDA0002312540640000093
3ab:R5＝(α-Me)cinnamyl；
3ac:R5＝3-Phenylpropargyl；
3ad:R5＝Et；
3ae:R5＝Bn；
3af:R5＝tBu。
To a dry glass vial equipped with a stirrer was added the corresponding N-alkenyl α -unsaturated nitrone 1(0.2mmol), scandium triflate (Sc (OTf)320 mol%, 0.04mmol), Eosin Y (Eosin Y, 20 mol%) and 2mL of organic solvent (wherein the organic solvent used for the target compound 3ab-3ae is acetone, chloroform, N-hexane and dioxane respectively and the organic solvent used for the target compound 3af is carbon tetrachloride) were added to the vial, the vial was closed with a preservative film, then the vial containing the mixture was stirred at room temperature and reacted under irradiation of a white LED lamp (14W) for 3-7 days until N-alkenyl α -unsaturated nitrone 1 was completely consumed (monitored by TLC). at this time, the resulting reaction was depressurized to remove the solvent, and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate: 30: 1-10: 1, volume ratio) to give the target product 3. different target products and their characterization are as follows:
3 ab: pale yellow solid, 77mg, 69% yield; mp 138-139 ℃;1H NMR(400MHz,CDCl3):δ7.37(d,J＝7.6Hz,2H),7.32–7.14(m,11H),7.00(d,J＝7.2Hz,2H),6.51(s,1H),5.87–5.83(m,1H),5.68–5.63(m,1H),5.51–5.46(m,1H),4.70(d,J＝12.0Hz,1H),4.57(d,J＝12.0Hz,1H),4.02(s,1H),3.39–3.38(m,1H),2.79–2.74(m,1H),1.94(s,3H),1.76(s,3H),1.51(d,J＝7.2Hz,3H),1.30–1.25(m,1H),1.19–1.15(m,1H),1.10–1.06(m,1H),0.85–0.81(m,1H)；13C NMR(100MHz,CDCl3):δ172.4,169.5,142.8,136.6,136.4,135.5,131.9,129.6,129.3,128.8,128.5,128.2,128.1,127.9,127.8,126.8,126.4,125.0,79.8,77.6,70.8,62.8,50.9,49.8,45.9,21.6,15.6,12.5,11.1,9.3；IR(thin film)3023,2965,1736,1492,1148,1026,699cm-1；HRMS(ESI)m/z calcd for C36H38NO5[M+H]+564.2744 and found 564.2738, the structural formula is as follows:
Figure BDA0002312540640000101
3 ac: pale yellow solid, 84mg, 77% yield; mp 150-151 deg.C;1H NMR(400MHz,CDCl3):δ7.37(d,J＝7.6Hz,2H),7.30–7.24(m,7H),7.18–7.13(m,4H),7.00(d,J＝6.4Hz,2H),5.86–5.83(m,1H),5.75–5.72(m,1H),5.50–5.47(m,1H),4.93–4.83(m,2H),4.11(s,1H),3.36–3.35(m,1H),2.75–2.70(m,1H),1.96(s,3H),1.52(d,J＝7.2Hz,3H),1.26–1.16(m,2H),1.09–1.04(m,1H),0.89–0.85(m,1H)；13C NMR(100MHz,CDCl3):δ172.4,168.9,142.8,136.3,135.2,131.7,129.3,128.7,128.5,128.3,128.2,127.9,127.8,126.4,124.8,121.7,86.8,82.1,79.8,77.3,62.7,53.0,50.8,48.9,46.1,21.7,12.2,11.2,9.3；IR(thin film)3021,2954,2217,1735,1490,1145,1026,693cm-1；HRMS(ESI)m/z calcd for C35H34NO5[M+H]+548.2431 and found 548.2432, the structural formula is as follows:
Figure BDA0002312540640000111
3 ad: pale yellow solid, 70mg, 76% yield; mp: 133-134 deg.C;1H NMR(400MHz,CDCl3):δ7.37(d,J＝7.2Hz,2H),7.29–7.16(m,6H),7.03–7.02(m,2H),5.85–5.80(m,1H),5.65–5.62(m,1H),5.54–5.48(m,1H),4.14(q,J＝6.8Hz,2H),3.97(s,1H),3.36–3.35(m,1H),2.78–2.72(m,1H),1.95(s,3H),1.51(d,J＝6.8Hz,3H),1.28–1.25(m,1H),1.23(t,J＝7.2Hz,3H),1.18–1.13(m,1H),1.07–1.02(m,1H),0.82–0.76(m,1H)；13C NMR(100MHz,CDCl3):δ172.4,169.6,142.9,136.5,135.4,129.3,128.5,128.2,127.9,127.8,126.4,124.8,79.8,77.6,62.8,60.8,50.8,49.5,45.9,21.6,14.0,12.4,11.2,9.3；IR(thin film)3023,2968,1725,1651,1452,1248,1035,697cm-1；HRMS(ESI)m/z calcd for C28H32NO5[M+H]+462.2275 and found 462.2272, the structural formula is as follows:
Figure BDA0002312540640000112
3 ae: pale yellow solid, 73mg, 70% yield; mp is 88-89 ℃;1H NMR(400MHz,CDCl3):δ7.35(d,J＝7.6Hz,2H),7.27–7.16(m,11H),6.98(d,J＝6.8Hz,2H),5.84–5.80(m,1H),5.55–5.53(m,1H),5.46–5.42(m,1H),5.13(d,J＝12.0Hz,1H),5.03(d,J＝12.0Hz,1H),4.02(s,1H),3.34–3.33(m,1H),2.74–2.69(m,1H),1.92(s,3H),1.49(d,J＝7.2Hz,3H),1.27–1.15(m,1H),1.13–1.10(m,1H),1.06–1.01(m,1H),0.80–0.74(m,1H)；13C NMR(100MHz,CDCl3):δ172.3,169.5,142.8,136.4,135.4,135.0,129.3,128.6,128.5,128.4,128.3,128.2,127.9,127.8,126.4,124.8,79.7,77.4,66.7,62.7,50.8,49.3,45.9,21.6,12.3,11.1,9.3；IR(thin film)3032,2955,1733,1493,1149,1000,699cm-1；HRMS(ESI)m/z calcd forC33H34NO5[M+H]+524.2431 and found 524.2429, the structural formula is as follows:
Figure BDA0002312540640000113
3 af: pale yellow solid, 55mg, 56% yield; mp: 134-135 deg.C;1H NMR(400MHz,CDCl3):δ7.36(d,J＝7.6Hz,2H),7.28–7.15(m,6H),7.04–7.03(m,2H),5.83–5.78(m,1H),5.70–5.68(m,1H),5.52–5.50(m,1H),3.82(s,1H),3.36–3.35(m,1H),2.79–2.73(m,1H),1.94(s,3H),1.50(d,J＝7.2Hz,3H),1.40(s,9H),1.29–1.21(m,1H),1.18–1.12(m,1H),1.06–1.00(m,1H),0.88–0.83(m,1H)；13CNMR(100MHz,CDCl3):δ172.3,168.9,142.9,136.5,136.1,129.3,128.5,128.2,127.9,127.4,126.3,124.6,81.7,79.7,77.7,62.8,50.8,50.2,45.8,27.9,21.6,12.5,10.9,9.3；IR(thin film)3022,2968,1725,1491,1142,1072,700cm-1；HRMS(ESI)m/z calcd for C30H36NO5[M+H]+490.2588 and found 490.2587, the structural formula is as follows:
Figure BDA0002312540640000121
example 3
The 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxide cyclononane derivative provided by the invention is synthesized according to the following synthetic route.
Figure BDA0002312540640000122
3bf:R1＝(4-OMe)C6H5,R2＝(4-OMe)C6H5,R3＝Me,R4＝Me,R5＝tBu；
3hd:R1＝Ph,R2＝Ph,R3＝Ph,R4＝Et,R5＝Et。
To a dry glass vial equipped with a stir bar was added the corresponding N-alkenyl α -unsaturated nitrone 1(0.2mmol), copper triflate (Cu (OTf)220 mol%, 0.04mmol), Eosin Y (Eosin Y, 30 mol%) and 2mL of tert-butyl methyl ether, methylene cyclopropane 2(0.4mmol) was added to the vial, the vial was closed with a preservative film then the reaction mixture was stirred at 40 ℃ and irradiated under a white LED lamp (17W) for 3-7 days until the nitrone N-alkenyl α -unsaturation 1 was completely consumed (monitored by TLC). at this point, the resulting reaction was freed of solvent under reduced pressure and the residue was chromatographed on a silica gel column (petroleum ether/ethyl acetate: 30:1 to 10:1, volume ratio) to give the desired product 3. different target products and their characterization were as follows:
3 bf: pale yellow solid, 80mg, 73% yield; mp: 154-155 deg.C;1H NMR(400MHz,CDCl3):δ7.26–7.24(m,2H),6.97(d,J＝8.4Hz,2H),6.80(d,J＝8.0Hz,2H),6.72(d,J＝8.4Hz,2H),5.81–5.76(m,1H),5.72–5.60(m,1H),5.51–5.40(m,1H),4.03(s,1H),3.73(s,6H),3.35–3.30(m,1H),2.77–2.72(m,1H),2.35(s,9H),1.95(s,3H),1.46(d,J＝7.2Hz,3H),1.28–1.25(m,1H),1.19–1.13(m,1H),1.09–1.03(m,1H),0.88–0.81(m,1H)；13C NMR(100MHz,CDCl3):δ172.8,169.6,159.9,135.8,135.3,130.8,129.7,128.5,128.3,126.5,122.5,113.1,79.5,77.8,65.8,62.7,55.3,50.2,49.5,46.1,21.5,12.5,11.3,9.3；IR(thin film)3023,2948,1713,1445,1225,1021,695cm-1；HRMS(ESI)m/z calcd for C32H40NO7[M+H]+550.2799 and found 550.2800, the structural formula is as follows:
Figure BDA0002312540640000131
3 hd: pale yellow solid, 78mg, 73% yield; mp 160-161 deg.C;1H NMR(400MHz,CDCl3):δ7.43(d,J＝7.2Hz,2H),7.36–7.34(m,2H),7.26–7.01(m,8H),6.86(d,J＝6.8Hz,2H),6.04–5.97(m,1H),5.68–5.61(m,1H),5.59–5.56(m,1H),5.40–5.36(m,1H),4.14(q,J＝6.8Hz,2H),4.08(s,1H),3.43–3.40(m,1H),3.10–3.07(m,1H),2.48–2.40(m,1H),2.14–2.09(m,1H),1.28–1.17(m,2H),1.16(t,J＝6.8Hz,3H),1.04–1.01(m,1H),0.82–0.81(m,1H),0.78(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ172.0,169.2,142.9,136.7,136.4,135.7,135.3,129.8,129.3,128.6,128.2,127.8,126.9,126.5,124.5,122.0,79.5,77.6,65.3,63.4,53.6,51.6,49.1,21.3,22.1,13.4,11.1,9.3；IR(thin film)3025,2950,1733,1490,1151,965,696cm-1；HRMS(ESI)m/z calcd for C34H36NO5[M+H]+538.2588 and found 538.2586, the structural formula is as follows:
Figure BDA0002312540640000132
experimental example 1: the in vitro anti-inflammatory activity experiment of the 1, 2-dioxirane [3,4-f ] nitrogen oxo cyclononane derivative
Test for determining activity of compound and control drug indometacin on RAW264.7 cells at concentration of 100 mu M by using MTT method
1. Digestion and inoculation of test cells: culturing test cells RAW264.7 (mouse mononuclear macrophage leukemia cells) to logarithmic phase, digesting with 0.25% trypsin, adding culture medium containing 10% fetal calf serum, blowing uniformly with sterile plastic pipette to form single cell suspension, inoculating to 96-well plate, adding 180. mu.L of each well, adding 200. mu.L of PBS buffer around 96-well plate to reduce culture medium evaporation.
2. And (3) adding drugs to the cell strain, namely adding 20 mu L of drugs to each hole when the cells in the holes grow to occupy about 70% of the whole hole area, diluting the drugs to 100 mu M, tapping by hands, setting 5 multiple holes (parallel experiments), setting blank holes (without drugs) and zero adjusting holes (culture medium containing 10% fetal calf serum) in each 96-hole plate, continuously putting the 96-hole plate into an incubator, and observing the survival condition of the cells under a microscope.
3. And (3) testing a plate: after the medicine is added and the culture is continued for 48 hours, 10 mu L of MTT is added into each hole for staining, the cell is tapped by hands, the culture is continued for 4-6 hours, then the culture medium in each hole is discarded, 100 mu L of DMSO is added into each hole, the micro oscillator is placed on the cell and is oscillated for 10min, the generated formazan is fully dissolved, the cell is moved to an enzyme linked immunosorbent assay detector to detect the light absorption value of each hole, and the PASW software is used for processing data. The results are shown in Table 1.
TABLE 1 MTT assay for the Effect of Compounds on RAW264.7 cell viability
Figure BDA0002312540640000141
The compounds 3ba,3fa were tested for NO because of their high relative survival at a concentration of 100 μ M.
Secondly, the Griess method is used for determining the inhibition effect of partial low-toxicity compounds on the release of NO from mouse macrophage RAW264.7 induced by Lipopolysaccharide (LPS)
The compounds 3ba,3fa showed very low toxicity to mouse macrophage RAW264.7, so the applicant further tested the effect of these compounds on inhibition of Lipopolysaccharide (LPS) induced release of NO from mouse macrophage RAW264.7, and the experimental results:
1. inoculation and pretreatment of cells: RAW264.7 cells (mouse mononuclear macrophage leukemia cells) growing to a logarithmic growth phase are inoculated into a 24-well culture plate, 400 mu L of each well is provided with a control group, an LPS stress model group (1 mu g/mL LPS) and drug experimental groups (6.25, 12.5, 25 and 50 mu g/m L) with different concentrations, culture media with 0.1% DMSO (final concentration) are added into the control group and the LPS stress model group, the experimental groups are pretreated for 1h by drug solutions with different concentrations and then treated for 24h by adding 1 mu g/mL LPS, and cell supernatants are collected.
Measuring the NO release amount by a Griess method: taking the diluted serial concentration gradient standard reagent and the cell culture supernatant to be detected into a 96-well plate, wherein each well is 0.05mL, and the operation is carried out according to the kit instructions, and the specific steps are as follows:
(1) the reaction mixture was added to 0.05mL of Griess reagent 1 per well at room temperature, and the mixture was allowed to stand for 10 min.
(2) The reaction mixture was added to 0.05mL of Griess reagent 2 per well at room temperature, and the mixture was allowed to stand for 10 min.
(3) And (4) measuring the light absorption value at 540nm to obtain a standard curve, and determining the concentration of NO in the sample to be measured.
The test results are shown in Table 2.
The ability of compounds 3aa,3ba,3ca,3fa,3ha,3ac to inhibit LPS-induced release of mouse macrophage NO at a concentration of 6.25 μ M was examined by Griess method.
TABLE 2 Effect of different compounds on NO release from RAW264.7 cells at the same concentration (6.25. mu.M)
Figure BDA0002312540640000142
As can be seen from table 2, most of the compounds showed good inhibitory effect on the release of NO from RAW264.7 cells compared to indomethacin, and especially the compounds 3ba and 3fa showed good anti-inflammatory activity.

Claims (10)

1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0002312540630000011
wherein:
R1represents a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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 a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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;
R3is represented by 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 a hydrogen atom, 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);
R5is represented by C1～8Alkyl of (C)1～6Alkoxy or C1～4The perfluoroalkyl group of (a) is a perfluoroalkyl group,or is unsubstituted, mono-or di-substituted phenyl; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl group or halogen atom of (2).
2. A method of synthesizing the compound of claim 1, wherein: the method mainly comprises the following steps: placing a compound shown as a formula (II), a compound shown as a formula (III), a photosensitizer and a catalyst in an organic solvent, and reacting under the irradiation of lamplight in the presence of oxygen to obtain a crude product of a target compound;
Figure FDA0002312540630000012
wherein:
R1represents a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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 a hydrogen atom, a halogen atom, C1～4Alkyl of (C)1～4Alkoxy or C1～4Or an unsubstituted, mono-, di-, tri-, tetra-or pentasubstituted 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;
R3is represented by 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)1～4OfFluoroalkyl radical, C1～6Alkyl or halogen atom of (a);
R4represents a hydrogen atom, 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);
R5is represented by 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);
the catalyst is one or the combination of more than two of copper salt, ytterbium salt and scandium salt.
3. The method of synthesis according to claim 2, characterized in that: the photosensitizer is eosin Y.
4. The method of synthesis according to claim 2, characterized in that: the copper salt is one or the combination of more than two of cupric bromide, cupric iodide, cupric chloride, copper sulfate, acetic acid ketone, copper trifluoromethanesulfonate, cuprous bromide, cuprous iodide and cuprous chloride; the ytterbium salt is ytterbium trifluoromethanesulfonate; the scandium salt is scandium trifluoromethanesulfonate.
5. The method of synthesis according to claim 2, characterized in that: the organic solvent is one or the combination of more than two of toluene, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, tert-butyl methyl ether, dichloromethane, acetone, trichloromethane and dioxane.
6. The method of synthesis according to claim 2, characterized in that: the reaction is carried out under the irradiation of a white light LED lamp.
7. The method of synthesis according to claim 2, characterized in that: the reaction is carried out at a temperature below 80 ℃.
8. The synthesis method according to any one of claims 2 to 7, wherein: also comprises a step of purifying the crude product of the target compound.
9. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammation.
10. A pharmaceutical composition characterized by: comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
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Citations (1)

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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432126A (en) * 2016-09-18 2017-02-22 广西师范大学 1-oxy-2,8-diazacyclononane derivatives and synthetic method thereof
CN108623530A (en) * 2016-09-18 2018-10-09 广西师范大学 1,2,8- oxo diazacyclo nonyl- 9- 40 thione derivatives and its synthetic method and application
CN108727293A (en) * 2016-09-18 2018-11-02 广西师范大学 1,2,8- oxo diazacyclo nonyl- 9- ketone derivatives and its synthetic method
CN108752286A (en) * 2016-09-18 2018-11-06 广西师范大学 1,2,8- oxo diazacyclo nonane derivatives and its synthetic method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
邹宁，等: "N-烯基-α,β-不饱和硝酮与异氰酸酯合成二氮杂环壬烷", 《中国化学会第十三届全国有机合成化学学术研讨会论文摘要集》 *
马小盼: "硝酮的合成及其在氮杂环构筑中的应用研究", 《广西师范大学硕士学位论文》 *

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