CN112142683B - Aza-eleven-membered ring compound, preparation method and application thereof, and medicine containing compound - Google Patents

Aza-eleven-membered ring compound, preparation method and application thereof, and medicine containing compound Download PDF

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CN112142683B
CN112142683B CN202010903944.5A CN202010903944A CN112142683B CN 112142683 B CN112142683 B CN 112142683B CN 202010903944 A CN202010903944 A CN 202010903944A CN 112142683 B CN112142683 B CN 112142683B
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李俊龙
戴青松
陶应茂
张翔
冷海军
向朋
黄华
李青竹
刘悦
漆婷
黄茂林
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Chengdu University
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Abstract

The invention discloses an aza-eleven-ring compound, which has the following structural general formula:

Description

Aza-eleven-membered ring compound, preparation method and application thereof, and medicine containing compound
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an aza-eleven-membered ring compound and a preparation method and application thereof.
Background
The unique molecular skeleton constituted by the middle ring structure has been a focus of great attention of chemists. However, most of the currently bioactive cyclic lactones exist only in natural products, and have various biological functions when a lactone group exists in the cyclic lactone. Although its unique 3D structure can provide a new reference for non-medicinal targets, these scaffolds are rarely found in the first 200 popular famous drugs and other approved active drugs. The main reason is that it is difficult to formulate an effective synthetic strategy and establish various cyclic lactone libraries for screening medicinal materials.
The conventional cyclic lactonization scheme is hampered by the unfavorable enthalpy and entropy factors of the cyclic structure. In recent years, other viable solutions have been explored, including metathesis ring-closing reactions, cleavage of fused bicyclic ring systems, free radical-mediated ring expansion and sigma rearrangement. However, most of these methods still rely heavily on the inherent properties of the particular substrate, and the overall synthesis yield is not generally high. Therefore, it would be desirable to develop a general scheme for the rapid and diversity-oriented synthesis of mesocyclic lactones in a one-step reaction using commercially available reagents and readily available materials.
Disclosure of Invention
In order to further explore compounds with a cyclolactone structure and enrich medicinal materials, the invention discloses an aza-eleven-ring compound and a preparation method and application thereof, aiming at exploring a suitable synthesis method of the cyclolactone compound, wherein the reaction condition is easy to operate, the yield is high, and the adopted raw material substrate is easy to obtain.
In order to achieve the purpose, the technical scheme disclosed by the invention is as follows: the invention discloses an azaeleven-membered ring compound, which has the following structural general formula:
Figure BDA0002660733850000011
preferably, said R1Including hydrogen, halogens, methyl, and methoxy.
Preferably, said R is2Including methyl, ethyl, allyl, benzyl.
Preferably, said R is3Including benzene rings, naphthalene rings, and substituted benzene rings.
The present invention also provides a process for the preparation of the aforementioned azaundecene ring compound, which comprises the steps of:
the chemical reaction formula of the method is as follows:
Figure BDA0002660733850000021
further, the preparation method specifically comprises the following steps: under the condition of argon, 1-2ml of toluene is used as a solvent, a tris (dibenzylideneacetone) dipalladium-chloroform adduct (0.025eq) and a (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) phosphine ligand (0.01eq) are coordinated, the solution is stirred at room temperature, after the solution turns from red to yellow, a substrate 1(1eq) and a substrate 2(1.5eq) are added, the reaction is carried out for 12 hours, a point plate monitoring is carried out, after the reaction is finished, an organic layer is concentrated, a chromatographic column is assembled, degreased cotton and 70-100 times of sample loading amount of silica gel are sequentially added, a sample is dissolved by dichloromethane (0.5-1ml), a dropper is used for loading, a petroleum ether/ethyl acetate system (20:1-5:1) is used for elution, a separation process is monitored by thin layer chromatography, product points are concentrated, and the product is solidified and dried to obtain a product 3.
R in the substrate 12When the methyl or ethyl is adopted, the synthesis method comprises the following steps:
the chemical reaction formula of the method is as follows:
Figure BDA0002660733850000022
taking 10-30ml of DMF as a solvent, adding isatoic anhydride (1eq), adding potassium carbonate (1.2eq) and methyl iodide or ethyl iodide (1.2eq), stirring for 16 hours, after the reaction is finished, adding water which is 3 times of the mixed solution after the reaction, stirring for 10 minutes, filtering to obtain a solid, drying, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by dichloromethane (0.5-1ml), loading by a dropper, eluting by a petroleum ether/ethyl acetate system (10:1-5:1), monitoring the separation process by thin-layer chromatography, concentrating a product point, solidifying and drying to obtain a substrate 1-1.
The R is2The method for preparing the substrate 1, which is allyl or benzyl, comprises: the chemical reaction formula of the method is as follows:
Figure BDA0002660733850000031
adding isatoic anhydride (1eq) and 10-20ml of DMF, stirring for 15min under an ice bath, weighing sodium hydride (2eq) or (1.1eq) and diluting with DMF (2-5ml), adding into a flask, reacting for 30min, diluting benzyl bromide (1.05eq) or allyl bromide (1.1eq) with 2-5ml of DMF, adding into a constant pressure funnel, slowly dripping, adding 3 times of water to precipitate solid after the reaction is finished, filtering to obtain solid, drying, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample with dichloromethane (0.5-1ml), loading a dropper, eluting with a petroleum ether/ethyl acetate system (10:1-5:1), monitoring the separation process by thin-layer chromatography, concentrating the product point, solidifying and drying to obtain a substrate 1-2.
Further, the method for synthesizing the substrate 2 comprises the following steps:
(1) adding 50-60ml of solvent (acetonitrile: water is 4:1-5:1) into a (1eq), sequentially adding iodobenzene trifluoroacetate (2eq) and trifluoroacetic acid (2eq), condensing and refluxing for 2 hours at 80 ℃, monitoring the reaction by thin-layer chromatography, removing acetonitrile by rotary evaporation, extracting and concentrating by using dichloromethane, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by using dichloromethane (0.5-1ml), loading by using a dropper, eluting by using a petroleum ether/ethyl acetate system (10:1-2:1), monitoring and separating by thin-layer chromatography, concentrating product points, solidifying and drying to obtain a substrate b.
The chemical reaction formula of the step is as follows:
Figure BDA0002660733850000041
(2) adding tetrahydrofuran (5-10ml) into b (1eq), dropwise adding vinyl magnesium bromide (2.5eq) under an ice bath condition, reacting for 2 hours at room temperature, monitoring the reaction by thin-layer chromatography, quenching by a saturated ammonium chloride solution (10-20ml) under the ice bath condition after the reaction is finished, extracting by dichloromethane (3 x 10ml), concentrating, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by dichloromethane (0.5-1ml), loading by a dropper, eluting by a petroleum ether/ethyl acetate system (10:1-2:1), monitoring the separation process by thin-layer chromatography, concentrating product points, solidifying and drying to obtain a substrate c. The chemical reaction formula of the step is as follows:
Figure BDA0002660733850000042
(3) Under the condition of argon, adding dichloromethane (5-10ml) as a solvent into c (1eq), adding pyridine (4eq), slowly adding triphosgene (0.5eq) under an ice bath condition, reacting at room temperature for 2 hours, monitoring the reaction by thin layer chromatography, quenching saturated ammonium chloride solution (10-20ml) under the ice bath condition after the reaction is finished, extracting dichloromethane (3 x 10ml), concentrating, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by dichloromethane (0.5-1ml), loading by a dropper, eluting by a petroleum ether/ethyl acetate system (30:1-10:1), monitoring the separation process by thin layer chromatography, concentrating a product point, solidifying and drying to obtain a substrate d. The chemical reaction formula of the step is as follows:
Figure BDA0002660733850000043
the invention also discloses application of the compound in preparing antitumor drugs.
Of course, drugs comprising any of the above compounds in a pharmaceutically acceptable carrier are also within the scope of the present invention.
The invention has the beneficial effects that: the research on the compound with the intermediate ring structure is further intensive, the compound with the intermediate ring structure is found to have pharmaceutical activity, a preparation method capable of enlarging production and producing on a large scale is provided, the adopted reaction substrate raw materials are easy to obtain, the reaction conditions of the preparation method are easy to realize, the reaction time is shortened to the maximum extent, meanwhile, the high yield can be obtained, and the method is a milestone breakthrough and progress in the process of researching the compound with the intermediate ring structure.
Drawings
FIG. 1 is a crystal structure of a compound according to an embodiment of the present invention.
Detailed Description
The present invention is described in further detail below by way of specific examples. The reagents used in the present invention are commercially available, and are not specifically described, and the prior art or natural conditions at normal temperature and normal pressure are used.
The first embodiment is as follows: the invention provides an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000051
the R is1Is hydrogen, R2Is methyl, R3(Z) -1-methyl-6-phenyl-4, 7-dihydro-2H-benzo [ d ] in the form of a benzene ring][1,7]Dioxa [3 ]]An azaundecane-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000052
we defined it as the basic body, whose single crystal structure is shown in fig. 1, and whose data such as molecular structure are shown in the following table.
Figure BDA0002660733850000061
The chemical reaction formula of the method for preparing the compound is as follows:
Figure BDA0002660733850000062
under the condition of argon, taking toluene as a solvent, and taking 1ml of toluene, firstly coordinating tris (dibenzylideneacetone) dipalladium-chloroform adduct (0.025eq) with (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) phosphine ligand (0.01eq), stirring at room temperature, adding substrate 1(1eq) and substrate 2(1.5eq) after the solution turns from red to yellow, reacting for 12 hours, after the reaction is finished, concentrating an organic layer by point plate monitoring, assembling a chromatographic column, sequentially adding degreased cotton and 70 times of sample loading amount of silica gel (or 100 times of sample loading amount, 80 times of sample loading amount and 90 times of sample loading amount), dissolving a sample by dichloromethane (0.5ml), loading a dropper, eluting by a petroleum ether/ethyl acetate system (20:1-5:1), monitoring a separation process by thin layer chromatography, concentrating product points, solidifying and drying to obtain a product 3.
The synthesis method of the substrate 1 comprises the following steps:
the chemical reaction formula of the method is as follows:
Figure BDA0002660733850000071
taking 10ml of DMF as a solvent, adding isatoic anhydride (1eq), adding potassium carbonate (1.2eq) and iodomethane (1.2eq), stirring for 16 hours, after the reaction is finished, adding water which is 3 times of the mixed solution after the reaction, stirring for 10 minutes, filtering to obtain a solid, drying, assembling a chromatographic column, sequentially adding degreased cotton and silica gel with 70 times of sample loading amount, dissolving a sample by dichloromethane (0.5), loading by a dropper, eluting by a petroleum ether/ethyl acetate system (10:1-5:1), monitoring the separation process by a thin-layer chromatography, concentrating a product point, curing and drying to obtain a substrate 1-1.
By adopting the method, the recovery rate of the obtained basic body is 95 percent, the melting point is 115-117 ℃, the obtained basic body is a white solid, and the following data are the data of the nuclear magnetic hydrogen spectrum, the carbon spectrum, the molecular structure and the like obtained by mass spectrum detection:
1H NMR(600MHz,CDCl3)δ(ppm):7.55(d,J＝7.8Hz,1H),7.48–7.44(m,3H),7.38–7.35(m,2H),7.33–7.31(m,1H),7.24–7.23(m,2H),6.08(t,J＝7.2Hz,1H),5.23(br s,2H),4.67(s,2H),3.42(s,3H)。
13C NMR(150MHz,CDCl3)δ(ppm):167.8,154.1,145.7,141.0,140.7,131.2,130.0,128.5,128.1,127.4,126.7,125.4,124.5,64.1,61.5,38.1。
HRMS(ESI)m/z calculated for C19H17NO4+Na+346.1050 and found 346.1047. This compound was denoted as compound 001.
Example two: the invention discloses an aza eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000081
R1may be a halogen substituent, R2Is methyl, R3Is a benzene ring, e.g. (Z) -1-methyl-6-phenyl-12-chloro-4, 7-dihydro-2H-benzenebenzo [ d)][1,7]Dioxa [3 ] ]An azaundecano-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000082
the method for preparing the compound is the same as that of example one, and the method for synthesizing the substrate 1 is the same as that of example one.
Of course, in the specific synthesis, R1、R2、R3In agreement with the target product, although R of each compound is based on the general structural formula1、R2、R3Different, but all synthesized according to the principle of the preparation method of the invention.
The synthesis method of the substrate 2 comprises the following steps:
(1) adding 50-60ml of solvent (acetonitrile: water is 4:1-5:1) into a (1eq), sequentially adding iodobenzene trifluoroacetate (2eq) and trifluoroacetic acid (2eq), condensing and refluxing for 2 hours at 80 ℃, monitoring the reaction by thin-layer chromatography, removing acetonitrile by rotary evaporation, extracting and concentrating by using dichloromethane, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by using dichloromethane (0.5-1ml), loading by using a dropper, eluting by using a petroleum ether/ethyl acetate system (10:1-2:1), monitoring and separating by thin-layer chromatography, concentrating product points, solidifying and drying to obtain a substrate b. The chemical reaction formula of the step is as follows:
Figure BDA0002660733850000091
(2) under the condition of argon, adding tetrahydrofuran (5-10ml) into b (1eq), under the condition of ice bath, dropwise adding vinyl magnesium bromide (2.5eq), reacting for 2 hours at room temperature, monitoring the reaction by thin-layer chromatography, after the reaction is finished, quenching saturated ammonium chloride solution (10-20ml) under the condition of ice bath, extracting by dichloromethane (3 x 10ml), concentrating, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by dichloromethane (0.5ml), loading by a dropper, eluting by a petroleum ether/ethyl acetate system (10:1-2:1), monitoring the separation process by thin-layer chromatography, concentrating a product point, solidifying and drying to obtain a substrate c. The chemical reaction formula of the step is as follows:
Figure BDA0002660733850000092
(3) Under the condition of argon, adding dichloromethane (5-10ml) as a solvent into c (1eq), adding pyridine (4eq), slowly adding triphosgene (0.5eq) under an ice bath condition, reacting at room temperature for 2 hours, monitoring the reaction by thin layer chromatography, quenching saturated ammonium chloride solution (10-20ml) under the ice bath condition after the reaction is finished, extracting dichloromethane (3 x 10ml), concentrating, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by dichloromethane (0.5-1ml), loading by a dropper, eluting by a petroleum ether/ethyl acetate system (30:1-10:1), monitoring the separation process by thin layer chromatography, concentrating a product point, solidifying and drying to obtain a substrate d. The chemical reaction formula of the step is as follows:
Figure BDA0002660733850000093
similarly, in the preparation of substrate 2, R3As with the final product, R in compound d may be hydrogen or any substituent, and they are prepared according to the synthetic principle of the method of the present invention.
R obtained in this example1The recovery rate of the compound prepared by the method is 87%, the compound is semisolid, and the nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum data are as follows:
1H NMR(600MHz,CDCl3)δ(ppm):7.51(d,J＝7.8Hz,1H),7.46(d,J＝7.8Hz,2H),7.39–7.31(m,3H),7.24–7.18(m,2H),6.07(br s,1H),5.23(br s,2H),4.67(s,2H),3.41(s,3H)。
13C NMR(150MHz,CDCl3)δ(ppm):167.1,153.8,145.6,142.2,140.9,136.9,128.8,128.6,128.2,126.7,125.5,124.9,124.3,64.2,61.7,38.0。
HRMS(ESI)m/z calculated for C19H16ClNO4+Na+:380.0660(35Cl),382.0631(37cl), found:380.0659,382.0635. This compound was designated as compound 002.
Of course, other halogens R can be prepared according to the principle of the synthetic method of the embodiment1A substituted compound. Of course, R can be prepared by the same principle of the preparation method of the invention1Is halogen, R2Is any one of methyl, ethyl, allyl and benzyl, R3Any one of naphthalene ring and substituted benzene ring can be obtained according to the technical scheme disclosed by the invention obviously by the principle of the naphthalene ring and the substituted benzene ring, and the naphthalene ring and the substituted benzene ring are not repeated one by one for unnecessary repetitionAre listed.
Example three: the invention discloses an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000101
R1may be a methoxy substituent, R2Is methyl, R3Is a phenyl ring, e.g., (Z) -1-methyl-6-phenyl-12-methoxy-4, 7-dihydro-2H-benzo [ d][1,7]Dioxa [3 ]]An azaundecane-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000102
the process for the preparation of this compound is the same as in example one, substrate 1 is prepared by the same method as in example one, substrate 2 is prepared by the same method as in example two, R is obtained in this example1The recovery rate of the compound prepared by the method is 82%, the compound is semisolid, and the nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum data are as follows:
1H NMR(600MHz,CDCl3)δ(ppm):7.63(d,J＝8.4Hz,1H),7.46(d,J＝7.8Hz,2H),7.36(t,J＝7.2Hz,2H),7.33–7.29(m,1H),6.82–6.72(m,2H),5.98(t,J＝7.2Hz,1H),5.21(br s,2H),4.71(s,2H),3.84(s,3H),3.41(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.5,162.1,154.5,144.8,143.0,141.4,130.1,128.5,128.0,126.8,124.8,121.7,111.2,110.3,63.9,61.7,55.6,38.3.
HRMS(ESI)m/z calculated for C20H19NO5+Na+376.1155, found 376.1156, the compound is named as compound 003.
Of course, other positions R can be prepared according to the synthetic method principle of the embodiment1Methoxy substituted compounds. Of course, R can be prepared by the same principle of the preparation method of the invention1Is methoxy, R2Is methyl, ethyl,Any one of allyl and benzyl, R3Any one of naphthalene ring and substituted benzene ring can be obtained by the principle of the invention as is obvious to the technical scheme of the invention disclosure for the skilled person, and the description is not repeated for unnecessary repetition.
Example four: the invention discloses an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000111
R1may be a methyl substituent, R2Is methyl, R3Is a phenyl ring, e.g. (Z) -1, 11-dimethyl-6-phenyl-4, 7-dihydro-2H-benzo [ d ]][1,7]Dioxa [3 ]]An azaundecane-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000112
the process for preparing the compound is the same as in example one, the process for preparing substrate 1 is the same as in example one, and the process for preparing substrate 2 is the same as in example two.
R obtained in this example1The recovery rate of the compound prepared by the method is 74%, the compound is a light yellow solid, the melting point is 83-90 ℃, and the nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum data are as follows:
1H NMR(600MHz,CDCl3)δ(ppm):7.48(d,J＝7.8Hz,2H),7.39–7.35(m,3H),7.33–7.29(m,1H),7.28–7.24(m,1H),7.12(d,J＝8.4Hz,1H),6.08(t,J＝7.2Hz,1H),5.22(br s,2H),4.66(s,2H),3.39(s,3H),2.36(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.9,154.3,145.6,141.0,138.2,135.4,131.8,129.7,128.5,128.1,127.9,126.8,124.5,124.5,64.0,61.4,38.1,20.7.
HRMS(ESI)m/z calculated for C20H19NO4+Na+360.1206 and found 360.1194, the compound is recorded as a compoundSubstance 004.
Of course, other positions R can be prepared according to the synthetic method principle of the embodiment1The methyl-substituted compound can be prepared by adopting the principle of the preparation method of the invention to be any one of methyl 1, methyl 2, ethyl, allyl and benzyl, and R3 is any one of naphthalene ring and substituted benzene ring, and the principle is obviously obtained by the technical scheme disclosed by the invention for a person skilled in the art, and the methyl-substituted compound is not listed for unnecessary repetition.
Example five: the invention discloses an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000121
R1is hydrogen, R2Is ethyl, R3Is a phenyl ring, e.g. (Z) -1-ethyl-6-phenyl-4, 7-dihydro-2H-benzo [ d)][1,7]Dioxa [3 ]]An azaundecane-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000131
the process for the preparation of this compound is the same as in example one, the process for the preparation of substrate 1 is the same as in example one except that methyl iodide is replaced by ethyl iodide as the starting material, and the process for the preparation of substrate 2 is the same as in example two.
R obtained in this example2The recovery rate of the compound prepared by the method is 85 percent, the compound is a light yellow solid, the melting point is 109-113 ℃, and the nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum data are as follows:
1H NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝7.8Hz,1H),7.51–7.42(m,3H),7.36(t,J＝7.8Hz,2H),7.32(t,J＝7.2Hz,1H),7.29–7.21(m,2H),6.08(t,J＝7.2Hz,1H),5.21(br s,2H),4.66(s,2H),3.89(br s,2H),1.25(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.6,153.7,145.6,141.1,139.5,131.2,130.8,128.5,128.1,127.6,126.7,125.5,124.9,124.6,64.0,61.4,46.0,13.2.
HRMS(ESI)m/z calculated for C20H19NO4+Na+360.1206, found 360.1204 the compound is named as compound 005.
The principle of the preparation method of the invention is the same as that of preparing R1 which is any one of halogen, methyl and methoxy, R2 which is ethyl, R3 which is naphthalene ring or substituted benzene ring, and the principle is obviously obtained by the technical scheme disclosed by the invention for the skilled person, and the method is not listed for unnecessary repetition.
Example six: the invention discloses an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000132
R1is hydrogen, R2Is allyl, R3Is a phenyl ring, e.g. (Z) -1-allyl-6-phenyl-4, 7-dihydro-2H-benzo [ d)][1,7]Dioxa [3 ]]An azaundecane-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000141
the compound was prepared as in example one, substrate 1 was prepared by a method comprising:
the chemical reaction formula of the method is as follows:
Figure BDA0002660733850000142
adding isatoic anhydride (1eq) and 10-20ml of DMF, stirring for 15min under ice bath, weighing sodium hydride (1.1eq) and diluting with DMF (2-5ml), adding into a flask, reacting for 30min, adding allyl bromide (1.1eq) after diluting with 2-5ml of DMF, slowly dropping into a constant pressure funnel, adding 3 times of water to separate out solid after reaction is completed, filtering to obtain solid, drying, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample with dichloromethane (0.5-1ml), loading by a dropper, eluting with a petroleum ether/ethyl acetate system (10:1-5:1), monitoring the separation process by thin-layer chromatography, concentrating the product point, solidifying and drying to obtain a substrate 1-2. The preparation of substrate 2 was performed as in example two.
R obtained in this example2The recovery rate of the compound prepared by the method is 74 percent, the compound is a white solid, the melting point is 108-:
1H NMR(600MHz,CDCl3)δ(ppm):7.56(d,J＝6.6Hz,1H),7.48(d,J＝7.8Hz,2H),7.43(t,J＝7.8Hz,1H),7.37(t,J＝7.8Hz,2H),7.33(d,J＝7.2Hz,1H),7.32–7.28(m,1H),7.23(t,J＝7.8Hz,1H),6.10–6.00(m,2H),5.37–5.05(m,4H),4.68(br s,2H),4.43(br s,2H).
13C NMR(150MHz,CDCl3)δ(ppm):167.7,153.8,145.8,141.0,139.9,133.9,131.1,130.0,128.5,128.1,127.5,126.7,125.4,124.4,116.9,63.9,61.6,53.7.
HRMS(ESI)m/z calculated for C21H19NO4+Na+372.1206 and found 372.1211, the compound is marked as compound 006.
The principle of the preparation method of the invention is the same as that of preparing R1 which is any one of halogen, methyl and methoxy, R2 is allyl, R3 is naphthalene ring and substituted benzene ring, and the principle is obviously obtained by the technical scheme disclosed by the invention for the skilled person, and the method is not listed for unnecessary repetition.
Example seven: the invention discloses an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000151
R1is hydrogen, R2Is benzyl, R3Is a phenyl ring, e.g. (Z) -1-benzyl-6-phenyl-4, 7-dihydro-2H-benzo [ d)][1,7]Dioxa [3 ]]An azaundecano-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000152
the procedure for the preparation of this compound is the same as in example one, and for substrate 1 as in example six, except that allyl bromide is changed to benzyl bromide (1.05eq), sodium hydride (1.1eq) is weighed, and for substrate 2 as in example two.
R obtained in this example2The recovery rate of the compound prepared by the method is 68 percent, the compound is a white solid, the melting point is 170-173 ℃, and the nuclear magnetic hydrogen spectrum, the carbon spectrum and the mass spectrum data are as follows:
1H NMR(600MHz,CDCl3)δ(ppm):7.55(d,J＝7.2Hz,1H),7.48(d,J＝7.2Hz,2H),7.43–7.28(m,7H),7.25–7.23(m,2H),7.20(t,J＝7.2Hz,1H),7.15(d,J＝8.4Hz,1H),6.09(t,J＝7.2Hz,1H),5.40–4.91(m,4H),4.71(s,2H).
13C NMR(150MHz,CDCl3)δ(ppm):167.7,154.5,145.8,141.0,140.0,137.5,131.2,129.8,128.5,128.4,128.2,127.8,127.6,127.3,126.7,125.5,124.4,124.2,63.8,61.8,54.4.
HRMS(ESI)m/z calculated for C25H21NO4+Na+422.1363, found 422.1362, this compound is named compound 007.
The principle of the preparation method of the invention is the same as that of the preparation method of the invention to prepare R1Is any one of halogen, methyl and methoxy, R2Is benzyl, R3Any one of naphthalene ring and substituted benzene ring can be obtained by the principle of the invention as is obvious to the technical scheme of the invention disclosure for the skilled person, and the description is not repeated for unnecessary repetition.
Example eight: the invention discloses an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000161
R1may be hydrogen, R2Is methyl, R3Is a substituted benzene ring, e.g. (Z) -1-methyl-6- (4-chlorophenyl) -4, 7-dihydro-2H-benzo [ d)][1,7]Dioxa [3 ]]An azaundecane-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000162
the process for preparing the compound is the same as in example one, the process for preparing substrate 1 is the same as in example one, and the process for preparing substrate 2 is the same as in example two.
R obtained in this example3The recovery rate of the compound prepared by the method is 92 percent, the compound is a white solid, the melting point is 120-123 ℃, and the nuclear magnetic hydrogen spectrum, the carbon spectrum and the mass spectrum data are as follows:
1H NMR(600MHz,CDCl3)δ(ppm):7.55(d,J＝7.8Hz,1H),7.46(t,J＝7.2Hz,1H),7.41(d,J＝8.4Hz,2H),7.33(d,J＝7.8Hz,2H),7.24(d,J＝7.2Hz,2H),6.06(t,J＝6.6Hz,1H),5.18(br s,2H),4.65(s,2H),3.41(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.8,154.0,144.5,140.8,139.5,134.1,131.3,129.9,128.7,128.2,127.4,125.4,124.9,124.6,64.1,61.3,38.0.
HRMS(ESI)m/z calculated for C19H16ClNO4+Na+:380.0660(35Cl),382.0631(37Cl), found:380.0667,382.0636 this compound is identified as compound 008.
Of course, other substituted phenyl rings R may likewise be prepared according to the principles of the synthetic method of this example3The compound of (1). Of course, R can be prepared by the same principle of the preparation method of the invention1Is any one of hydrogen, halogen, methyl and methoxy, R2Is any of methyl, ethyl, allyl and benzylA, R3The substituted benzene rings are obviously obtained by the technical scheme disclosed by the invention for the principle of the substituted benzene rings, and are not listed again for unnecessary repetition.
Example nine: the invention discloses an aza-eleven-ring compound, which has the following structural general formula:
Figure BDA0002660733850000171
R1may be hydrogen, R2Is methyl, R3Is a naphthalene ring, e.g. (Z) -1-methyl-6- (naphthalen-2-yl) -4, 7-dihydro-2H-benzo [ d)][1,7]Dioxa [3 ]]An azaundecane-2, 9(1H) -dione having the formula:
Figure BDA0002660733850000172
the process for preparing the compound is the same as in example one, the process for preparing substrate 1 is the same as in example one, and the process for preparing substrate 2 is the same as in example two.
R obtained in this example3The recovery rate of the compound prepared by the method is 80%, the compound is a white solid, the melting point is 118-122 ℃, and the nuclear magnetic hydrogen spectrum, the carbon spectrum and the mass spectrum data are as follows:
1H NMR(600MHz,CDCl3)δ(ppm):7.92(s,1H),7.89–7.80(m,4H),7.60(t,J＝7.8Hz,2H),7.51–7.43(m,3H),7.24–7.21(m,1H),6.22(t,J＝6.6Hz,1H),5.34(br s,2H),4.73(s,2H),3.44(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.9,154.2,145.6,140.8,138.3,133.2,133.0,131.2,130.0,128.2,127.6,126.4,126.3,125.8,125.4,124.9,124.8,124.6,64.1,61.6,38.1.
HRMS(ESI)m/z calculated for C23H19NO4+Na+396.1206, found 396.1216, this compound is named as compound 009.
Of course, the present invention is adoptedThe principle of the preparation method is the same, and R can be prepared1Is any one of halogen, methyl and methoxy, R2Is any one of ethyl, allyl and benzyl, R3Naphthalene rings, which are obviously obtained by the skilled person in the art according to the technical scheme disclosed in the invention due to the principle thereof, are not listed again for the sake of unnecessary repetition.
The following tests illustrate the use of the compounds of the invention: anti-tumor study
1. Experimental tumor cell strain
The human breast cancer MB468 cell line, the human breast cancer SKBR3 cell line, the human breast cancer MB231 cell line and the mouse melanoma A375 cell line are all provided by the national focus laboratory of biological treatment of Sichuan university, and the tumor cells are all frozen and stored in the national focus laboratory of biological treatment of Sichuan university.
2. Experimental methods
2.1 preparation and treatment of cells
4 kinds of tumor cells are cultured in RPMI-1640 culture solution containing 10% inactivated newborn calf serum at 37 deg.C and 5% CO2Growing in incubator until 80% cell fusion, digesting with 0.1% pancreatin solution to obtain single cell suspension, adjusting cell concentration to 5 × 104/mL, uniformly inoculating into 96-well microplate, each group having 3 multiple wells and 100 μ l/well, placing at 37 deg.C saturation humidity and 5% CO 2After culturing in an incubator for 24h, adding culture solution with the same amount into a normal control group; a concentration gradient of test drug (100, 50, 25, 12.5, 6.25. mu.g/mL) was added, 3 replicates per concentration and experiments were performed in 2 replicates. After the drug and the cells act for 24 hours, 10 mu L of MTT solution (5mg/mL) is added into each hole, after the culture is continued for 4 hours, 100 mu L of DMSO is added into each hole, the mixture is shaken and uniformly mixed to ensure that the crystal is fully dissolved, the absorbance value (A value) is measured at the 490nm wavelength of an enzyme-labeling instrument, and the average value of each concentration group is taken.
2.2 measurement of tumor cell proliferation inhibition Rate
The cell proliferation inhibition rate was calculated according to the following formula: the cell growth inhibition ratio (%) × 100% (1-test group a value/control group a value). All experimental data were statistically analyzed using SPSS 13.0. Results of the experimentObtaining IC by Probit50The value is obtained.
3. Results of the experiment
TABLE 1 inhibition of growth of test cells by compounds of the invention
IC50(μg/mL) MB231 MB468 A375 SKBR3
Compound 001 46.55 42.13 44.33 47.21
Compound 002 49.31 32.11 33.75 43.96
Compound 003 41.90 52.81 32.22 47.85
Compound 004 49.37 55.81 40.63 56.27
Compound 005 44.81 55.36 38.07 54.52
Compound 006 31.36 33.59 32.77 56.52
Compound 007 31.57 30.94 11.91 13.62
Compound 008 28.66 48.92 22.14 19.59
Compound 009 38.87 45.09 32.73 45.36
Experimental results show that the compound has excellent anti-tumor effect. (the above value is more than 50 to have the antitumor effect).
In conclusion, the compound has the advantages of simple preparation method, mild reaction, high yield, excellent antitumor activity and wide market application prospect.
Of course, the antitumor drug prepared by the compound and the pharmaceutically acceptable carrier is also in the protection scope of the invention.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. An azaundecene ring compound having the following general structural formula:
Figure 315273DEST_PATH_IMAGE001
；
the R is1Selected from hydrogen, halogens, methyl, and methoxy;
the R is2Selected from methyl, ethyl, allyl, benzyl;
the R is3Selected from phenyl, naphthyl and 4-chlorphenyl.
2. A process for the preparation of an azaundecene ring compound of claim 1 comprising the steps of:
the chemical reaction formula of the method is as follows:
Figure 763572DEST_PATH_IMAGE003
the preparation method specifically comprises the following steps: under the condition of argon, 1-2 ml of toluene is used as a solvent, 0.025eq of tris (dibenzylideneacetone) dipalladium-chloroform adduct and 0.01 eq of (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) phosphine ligand are coordinated, the mixture is stirred at room temperature, after the solution turns from red to yellow, 11 eq of a substrate and 21.5 eq of the substrate are added, the reaction is carried out for 12 hours, a point plate is used for monitoring and the reaction is finished, an organic layer is concentrated, a chromatographic column is assembled, degreased cotton and 70-100 times of sample loading amount of silica gel are sequentially added, 0.5-1ml of dichloromethane is used for dissolving a sample, a dropper is used for loading, a petroleum ether/ethyl acetate system is used for eluting at a ratio of 20:1-5:1, the separation process is monitored by thin-layer chromatography, product points are concentrated, and are solidified and dried to obtain a product 3.
3. The method according to claim 2, wherein R in the substrate 1 is2In the case of methyl or ethyl, the synthesis method of the substrate 1-1 comprises the following steps:
the chemical reaction formula of the method is as follows:
Figure 74468DEST_PATH_IMAGE004
the method for preparing the substrate 1-1 specifically comprises: taking 10-30ml of DMF as a solvent, adding 1eq of isatoic anhydride, adding 1.2eq of potassium carbonate and 1.2eq of methyl iodide or ethyl iodide, stirring for 16 hours, after the reaction is finished, adding 3 times of water of a mixed solution after the reaction, stirring for 10 minutes, filtering to obtain a solid, drying, assembling a chromatographic column, sequentially adding degreased cotton and 70-100 times of sample loading amount of silica gel, dissolving a sample by 0.5-1ml of dichloromethane, loading by a dropper, eluting by a petroleum ether/ethyl acetate system 10:1-5:1, monitoring the separation process by a thin layer chromatography, concentrating a product point, solidifying and drying to obtain a substrate 1-1.
4. The method of claim 2, wherein R is2The method for preparing the substrate 1-2, which is allyl or benzyl, comprises:
the chemical reaction formula of the method is as follows:
Figure 14218DEST_PATH_IMAGE005
the method for preparing the substrate 1-2 specifically comprises the following steps: adding isatoic anhydride 1eq and 10-20ml DMF, stirring for 15min under ice bath, weighing sodium hydride 2eq or 1.1eq, diluting with 2-5ml DMF, adding into a flask, reacting for 30min, diluting benzyl bromide 1.05eq or allyl bromide 1.1eq with 2-5ml DMF, adding into a constant pressure funnel, slowly dripping, after the reaction is completed, adding water 3 times the amount of the mixture to separate out solid, filtering to obtain solid, drying, assembling a chromatographic column, sequentially adding degreased cotton and silica gel 70-100 times the amount of the mixture, dichloromethane 0.5-1ml of a dissolved sample, loading by a dropper, eluting with a petroleum ether/ethyl acetate system 10:1-5:1, monitoring the separation process by thin-layer chromatography, concentrating product points, curing, and drying to obtain a substrate 1-2.
5. The method of claim 2, wherein the substrate 2 is synthesized by a method comprising the steps of:
(1) adding acetonitrile, water and iodobenzene trifluoroacetate into the step a, then adding trifluoroacetic acid for reaction, condensing and refluxing, removing the acetonitrile by rotary evaporation after the reaction is finished, and then extracting by dichloromethane to obtain the step b, wherein the chemical reaction formula of the step is as follows:
Figure 359748DEST_PATH_IMAGE006
(2) under the condition of argon, adding tetrahydrofuran into the mixture b, dropwise adding vinyl magnesium bromide into the mixture, reacting at room temperature, quenching saturated ammonium chloride solution after the reaction is finished, and extracting by adopting dichloromethane to obtain a product c, wherein the chemical reaction formula of the step is as follows:
Figure 978948DEST_PATH_IMAGE007
(3) under the condition of argon, adding dichloromethane serving as a solvent into the step c, then adding pyridine, then slowly adding triphosgene, reacting at room temperature, quenching saturated ammonium chloride solution after the reaction is finished, extracting by adopting dichloromethane to obtain a substrate 2, and expressing by adopting a letter d, wherein the chemical reaction formula of the step is as follows:
Figure 527873DEST_PATH_IMAGE008
。
6. the preparation method of claim 5, wherein in the step (1), 50-60ml of acetonitrile, water =4:1-5:1 solvent, 2eq of iodobenzene trifluoroacetate and 2eq of trifluoroacetic acid are added into a 1eq, the mixture is condensed and refluxed for 2 hours at 80 ℃, the reaction is monitored by thin layer chromatography, acetonitrile is removed by rotary evaporation, dichloromethane is used for extraction and concentration, a chromatographic column is assembled, degreased cotton and 70-100 times of sample loading amount of silica gel are added in sequence, 0.5-1ml of dichloromethane is used for dissolving a sample, a sample is loaded by a dropper, a petroleum ether/ethyl acetate system 10:1-2:1 is eluted, the separation process is monitored by thin layer chromatography, product points are concentrated, and the substrate b is obtained by solidification and drying.
7. The preparation method of claim 5, wherein in the step (2), under the condition of argon, 5-10ml of tetrahydrofuran is added into b 1eq, 2.5eq of vinyl magnesium bromide is added dropwise under the condition of ice bath, the reaction is monitored by thin layer chromatography for 2 hours at room temperature, after the reaction is finished, under the condition of ice bath, 10-20ml of saturated ammonium chloride solution is quenched, 3 x 10ml of dichloromethane is extracted, the mixture is concentrated and assembled into a chromatographic column, degreased cotton and 70-100 times of sample loading amount of silica gel are sequentially added, 0.5-1ml of dichloromethane is used for dissolving the sample, the sample is loaded by a dropper, a petroleum ether/ethyl acetate system 10:1-2:1 is eluted, the separation process is monitored by thin layer chromatography, and the product is concentrated, solidified and dried to obtain the substrate c.
8. The preparation method of claim 5, wherein in the step (3), under argon gas conditions, 5-10ml of dichloromethane is added into c 1eq as a solvent, 4eq of pyridine is added, 0.5eq of triphosgene is slowly added under ice bath conditions, reaction is carried out for 2 hours at room temperature, thin layer chromatography is used for monitoring reaction, after the reaction is finished, under ice bath conditions, 10-20ml of saturated ammonium chloride solution is quenched, 3 x 10ml of dichloromethane is used for extraction and concentration, a chromatographic column is assembled, degreased cotton and 70-100 times of silica gel are sequentially added, 0.5-1ml of dichloromethane is used for dissolving a sample, a dropper is used for loading, a petroleum ether/ethyl acetate system is eluted at a ratio of 30:1-10:1, thin layer chromatography is used for monitoring separation processes, a product point is concentrated, and solidification and drying are carried out, so as to obtain the substrate d.
9. The use of a compound according to claim 1 for the preparation of a medicament for the treatment of breast cancer, melanoma.
10. A medicament containing a compound of claim 1, comprising a compound of claim 1, and a pharmaceutically acceptable carrier.
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