CN110105299B - Aryl ether substituted oxazolidinone carboxylic acid ester derivative and preparation method and application thereof - Google Patents
Aryl ether substituted oxazolidinone carboxylic acid ester derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an aromatic ether substituted oxazolidinone carboxylic ester derivative, and a preparation method and application thereof. The structure of the compound is shown as a formula (I); wherein Ar is 1 Is aryl, substituted aryl or polycyclic aryl; ar (Ar) 2 Is aryl, substituted aryl or substituted heterocyclic aryl; the substituted aryl and the substituted heterocyclic aryl are substituted by halogen, hydroxyl, aryl, polycyclic aromatic hydrocarbon and C 1‑3 Alkyl radical, C 1‑3 Haloalkyl or C 1‑3 One or more of alkoxy. The compound of the invention contains an anticancer and antibacterial core structural unit oxazolidinone, has good inhibition effect on gastric cancer AGS cells, and IC thereof 50 The values are all lower than 16 mu M; meanwhile, the compound disclosed by the invention has the beneficial effects of simple preparation method, low price and easy availability of the compound as a raw material, mild reaction conditions, few steps, high reaction speed, low cost, few generated wastes, simplicity and safety in operation, high atom economy, high selectivity, high yield and the like, and can be prepared into an anti-gastric cancer drug for application.
Description
Technical Field
The invention relates to the field of synthetic medicine chemical industry, in particular to an aromatic ether substituted oxazolidinone carboxylic ester derivative and a preparation method and application thereof.
Background
The oxazolidinone structure is a core structural unit of various anti-cancer drugs, is a totally synthesized antibacterial drug which is marketed after sulfonamide and quinolone antibacterial drugs are added, has a very wide antibacterial spectrum, and has a very good antibacterial effect on staphylococcus, vancomycin-resistant enterococcus and the like. Moreover, the oxazolidinone compound has good effect on strains with drug resistance, and brings eosin for treatment of drug resistance and multi-drug resistant bacterial infection, so that the synthesized oxazolidinone compound with higher antibacterial activity has great application prospect.
The first drug to be marketed containing oxazolidinones was first marketed in the United states in 2000. Because the action mechanism of the drug is quite unique, the drug does not have cross drug resistance when being used together with other drugs, and has shown advantages in clinical treatment of drug-resistant G + bacterial infection. Besides the antibacterial aspect, the antibacterial and anti-cancer medicine also has a plurality of applications in the aspects of tumor resistance, cancer resistance and the like. Therefore, they now develop into a very important class of synthetic drugs.
Based on the unique pharmacological activity, the aromatic ether-containing substituted oxazolidinone carboxylic ester derivatives also occupy an extremely important position in the aspects of new drug research and development and the like. Most of oxazolidinone derivatives reported today have complicated synthesis steps, and involve the defects that the intermediate process can generate chemical wastes which can not be recycled in the multi-step reaction, the time consumption is long, the cost is high, the atom economy is low and the like, so that the search for an efficient, rapid and green synthesis way to obtain oxazolidinone derivatives is very important.
Disclosure of Invention
The invention aims to provide a carboxylic ester derivative containing aromatic ether substituted oxazolidinone, aiming at overcoming the defects and shortcomings in the prior art. The structure of the compound of the invention contains an oxazolidinone structure, which has good inhibition effect on gastric cancer AGS cells, and IC thereof 50 The values are all lower than 16 mu M, show good gastric cancer cell resistance, and can be prepared into anti-gastric cancer drugs for application.
The invention also aims to provide a preparation method of the aromatic ether substituted oxazolidinone carboxylic ester derivative.
The invention also aims to provide application of the carboxylic ester derivative containing the aromatic ether substituted oxazolidinone.
The above object of the present invention is achieved by the following scheme:
a carboxylic ester derivative containing aryl ether substituted oxazolidinone is disclosed, wherein the structure of the compound is shown as formula (I):
wherein Ar 1 Is aryl, substituted aryl or polycyclic aryl;
Ar 2 is aryl, substituted aryl or substituted heterocyclic aryl;
said aryl group is C 6-10 Aryl of (a);
the polycyclic aryl is a hydrocarbon containing more than two benzene rings;
the heterocyclic radical being C containing oxygen, sulfur or nitrogen atoms 5-6 Aryl of (a);
the substituted aryl and the substituted heterocyclic aryl refer to halogen, hydroxyl, aryl, polycyclic aromatic hydrocarbon and C 1-3 Alkyl radical, C 1-3 Haloalkyl or C 1-3 One or more of alkoxy.
Preferably, ar is 1 Is phenyl, substituted phenyl, naphthalene, anthracene, phenanthrene or pyrene; ar is 2 Is phenyl or substituted phenyl; wherein the substituent in the substituted phenyl is halogen, hydroxyl, C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 One or more of alkoxy or phenyl.
Preferably, ar is 1 Is phenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethyl-4-bromophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-hydroxyphenyl, p-biphenylyl, 2-naphthyl, 4- (9-anthryl) phenyl, 4- (1-naphthyl) phenyl, 4- (9-phenanthryl) phenyl or 4- (1-pyrenyl) phenyl, 5,6,7,8-tetrahydronaphthyl;
ar is 2 Is phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 2-naphthylnaphthyl。
Preferably, ar is 1 Is phenyl, 4-bromophenyl, 4-fluorophenyl, p-biphenyl, 4- (9-anthryl) phenyl or 4- (9-phenanthryl) phenyl; ar is 2 Is phenyl or 4-chlorophenyl.
More preferably, ar is 1 Is a p-biphenylyl group; ar is 2 Is phenyl.
The invention also discloses a preparation method of the aryl ether substituted oxazolidinone carboxylic ester derivative, and Ar is used 1 -OH、
Using (acetonitrile) [ (2-biphenyl) di-tert-butylphosphine as raw material, molecular sieve as water absorbent]Using hexafluoroantimonate gold (I) as a catalyst, firstly, ar 1 Dissolving OH, a water absorbent and a catalyst in an organic solvent to prepare a solution A,
mixing and dissolving the mixed solution in an organic solvent to prepare a solution B, and then dropwise adding the solution B into the solution A for reaction to obtain a target product;
wherein Ar 1 Is aryl, substituted aryl or polycyclic aryl; ar (Ar) 2 Is aryl, substituted aryl or substituted heterocyclic aryl;
the substituted aryl and the substituted heterocyclic aryl are substituted by halogen, hydroxyl, aryl, polycyclic aromatic hydrocarbon and C 1-3 Alkyl radical, C 1-3 Haloalkyl or C 1-3 One or more of alkoxy.
The course of the reaction is as follows:
the reaction principle is as follows:
the preparation method of the invention uses Ar 1 -OH、
The aryl ether substituted oxazolidinone carboxylic ester derivative is prepared by one-step reaction of the raw materials; compared with the existing reported synthesis method, the method takes the compounds which are available in the market or are easy to synthesize as raw materials, and the reaction has the characteristics of simple operation, mild condition, few steps, high reaction speed, low cost, less generated waste, high atom economy and the like.
In the process of mixing and reacting the solution A and the solution B, the target product can be well obtained only when the solution B is dripped into the solution A, and the target product cannot be obtained or almost cannot be obtained when the solution A is dripped into the solution B or the solution A and the solution B are directly mixed.
Preferably, during the reaction, ar 1 -OH、
And the molar ratio of the reaction with the catalyst is 1.0-1.5. During the reaction, when the raw materials
When the dosage of (2) is too much and exceeds the range, side reactions are increased, byproducts are increased, the atom economy is not met, and the yield of the final target product is influenced; when the proportion of the reaction raw materials is within the above range, the by-products are minimized, and the final target product has a higher yield, which is in line with atom economy.
More preferably, during the reaction, ar 1 -OH、
And the molar ratio of reaction of the catalyst is 1.0.
Preferably, the molecular sieve is
And (3) a molecular sieve.
Preferably, the dosage of the water absorbent is 50.0-100 mg/mmol based on the dosage of the phenol compound; the dosage of the organic solvent is 0.5 mL-1.0 mL/mmol.
More preferably, the water absorbing agent is charged in an amount of 50.0/mmol based on the amount of the phenol compound; the dosage of the organic solvent is 1.0mL/mmol.
Preferably, the temperature of the reaction is-40 ℃ to 40 ℃; the reaction time is 0.5 to 3.0 hours; the organic solvent is toluene, benzene, xylene, chlorobenzene, dichloromethane, trichloromethane or ethyl acetate. When the reaction temperature is in the range of-40 ℃ to 40 ℃, the target product can be obtained.
More preferably, the temperature of the reaction is 25 ℃; the reaction time was 1.0h. When the reaction temperature is 25 ℃, the yield of the target product is higher, heating is not needed, the operation is simple, and the energy consumption is low.
The application of the carboxylic ester derivative containing aryl ether substituted oxazolidinone in preparing anticancer drugs is also within the protection scope of the invention.
Preferably, the anti-cancer drug is a gastric cancer suppressing drug.
More preferably, the anticancer drug is a drug inhibiting gastric cancer AGS cells.
Compared with the prior art, the invention has the following beneficial effects:
the compound of the invention contains an anticancer and antibacterial core structural unit oxazolidinone, has good inhibition effect on gastric cancer AGS cells, and IC thereof 50 The values are all lower than 16 mu M, show good gastric cancer cell resistance, and can be prepared into anti-gastric cancer drugs for application.
Meanwhile, the preparation method of the compound is simple, the compound which is cheap and easy to obtain is used as a raw material, and the compound has the beneficial effects of mild reaction conditions, few reaction steps, quick reaction, low cost, less generated waste, simplicity and safety in operation, high atom economy, high selectivity, high yield and the like.
The compound is simple to prepare, low in cost, has a good inhibition effect on gastric cancer cells, and has a great application prospect in the aspect of preparing gastric cancer treatment medicines.
Drawings
FIG. 1 is a single crystal diffraction pattern of methyl (E) -2- ((4 '-iodo- [1,1' -biphenyl ] -4-oxo) -5- (2-oxazolidinone) -2-phenyl-4-pentenoate of example 6 of the present invention.
FIG. 2 shows the product obtained in example 1 1 H NMR scheme.
FIG. 3 shows the product obtained in example 1 13 Schematic C NMR.
FIG. 4 shows the product obtained in example 2 1 H NMR scheme.
FIG. 5 shows the product obtained in example 2 13 Schematic C NMR.
FIG. 6 shows the product obtained in example 3 1 H NMR scheme.
FIG. 7 shows the product obtained in example 3 13 C NMR is a schematic drawing.
FIG. 8 shows the product obtained in example 4 1 H NMR scheme.
FIG. 9 shows the product obtained in example 4 13 Schematic C NMR.
FIG. 10 shows the results of example 5 1 H NMR scheme.
FIG. 11 shows the product obtained in example 5 13 C NMR is a schematic drawing.
FIG. 12 shows the results obtained in example 6 1 H NMR scheme.
FIG. 13 shows the results of example 6 13 Schematic C NMR.
FIG. 14 shows the results of example 7 1 H NMR scheme.
FIG. 15 shows the results of example 7 13 Schematic C NMR.
FIG. 16 shows the product obtained in example 8 1 H NMR scheme.
FIG. 17 shows the product obtained in example 8 13 Schematic C NMR.
FIG. 18 shows the results of example 8 19 F NMR scheme.
FIG. 19 shows the results of example 9 1 H NMR scheme.
FIG. 20 shows the results of example 9 13 Schematic C NMR.
FIG. 21 shows the product obtained in example 10 1 H NMR scheme.
FIG. 22 shows the results of example 10 13 Schematic C NMR.
FIG. 23 shows the results of example 11 1 H NMR scheme.
FIG. 24 shows the product obtained in example 11 13 C NMR is a schematic drawing.
FIG. 25 shows the results of example 12 1 H NMR scheme.
FIG. 26 shows the results of example 12 13 Schematic C NMR.
FIG. 27 is a graph showing the activity of the product obtained in example 3.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
EXAMPLE 1 preparation of Compound a
The structure of compound a is shown below:
the preparation process comprises the following steps:
(1) P-bromophenol (0.40 mmol), (acetonitrile) [ (2-biphenyl) di-tert-butylphosphine]5.0mol percent of gold (I) hexafluoroantimonate,
Dissolving a molecular sieve in 4.0mL of dry dichloromethane to prepare a mixed solution A;
(2) Diazoacetate (0.48 mmol) and 3- (1,3-allene) -2-oxazolidinone (0.48 mmol) were dissolved in 2.0mL dry dichloromethane to make mixed solution B;
(3) Adding the mixed solution B into the mixed solution A by using a syringe pump for 1 hour at room temperature; stirring vigorously; after the addition of the mixed solution B, the mixture was stirred at room temperature for 60 minutes.
After the reaction is finished, filtering to obtain filtrate, evaporating the solvent, purifying the crude product by column chromatography to obtain a pure product, and performing column chromatography on the crude product (taking ethyl acetate: petroleum ether =1: 10-1:2 as an eluent) to obtain the pure product which is colorless oily matter. The structure is shown in formula (a), and the separation yield of the product is 62%. Of the product 1 The H NMR is shown in FIG. 2, which 13 The C NMR chart is shown in FIG. 3.
1 H NMR(400MHz,CDCl 3 )δ7.56–7.50(m,2H),7.34(tdd,J＝6.9,4.6,2.1Hz,3H),7.27–7.23(m,2H),6.67–6.60(m,2H),6.55(d,J＝14.4Hz,1H),4.57(dt,J＝14.5,7.4Hz,1H),4.36(t,J＝8.1Hz,2H),3.71(s,3H),3.56(td,J＝8.0,5.5Hz,2H),3.17(ddd,J＝14.8,8.0,1.0Hz,1H),3.08(ddd,J＝14.8,6.8,1.0Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ171.6,155.2,154.4,138.1,132.0,128.6,128.4,127.3,126.2,120.0,114.2,102.9,85.4,62.1,52.8,42.4,38.4.HRMS(ESI)[M+Na] + calcd for C 21 H 20 NO 5 Br,468.0417,found 468.0421.
EXAMPLE 2 preparation of Compound b
The structure of compound b is shown below:
compound b was prepared as a colorless oil in 66% isolated yield with reference to example 1, except that phenol was used instead of p-bromophenol. Of the product 1 The H NMR is shown in FIG. 4, which 13 The C NMR chart is shown in FIG. 5.
1 H NMR(400MHz,CDCl 3 )δ7.57(dd,J＝5.3,3.3Hz,2H),7.39–7.33(m,2H),7.33–7.28(m,1H),7.21–7.15(m,2H),6.93(t,J＝7.4Hz,1H),6.78(dd,J＝8.7,0.9Hz,2H),6.48(d,J＝14.4Hz,1H),4.55(dt,J＝14.5,7.4Hz,1H),4.33(t,J＝8.2Hz,2H),3.70(s,3H),3.59–3.47(m,2H),3.23(ddd,J＝14.8,7.9,0.8Hz,1H),3.11(ddd,J＝14.8,6.9,1.1Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ172.1,155.2,155.1,138.7,129.2,128.5,128.1,127.1,126.1,121.9,118.2,103.1,84.9,62.1,52.8,42.4,37.56.HRMS(ESI)[M+Na] + calcd for C 21 H 21 NO 5 ,390.1312,found 390.1312.
EXAMPLE 3 preparation of Compound c
The structure of compound c is shown below:
the procedure was as in example 1 except that p-phenylphenol was used instead of p-bromophenol to give compound c as a white solid in an isolated yield of 88%. Of the product 1 The H NMR is shown in FIG. 6, which 13 The C NMR chart is shown in FIG. 7.
1 H NMR(500MHz,CDCl 3 )δ7.59(d,J＝7.8Hz,2H),7.50(d,J＝7.8Hz,2H),7.41(d,J＝8.7Hz,2H),7.38(t,J＝7.7Hz,4H),7.32(d,J＝7.3Hz,1H),7.28(dd,J＝13.8,6.3Hz,1H),6.84(d,J＝8.7Hz,2H),6.54(d,J＝14.3Hz,1H),4.59(dt,J＝14.5,7.4Hz,1H),4.33(t,J＝8.1Hz,2H),3.72(s,3H),3.60–3.49(m,2H),3.25(dd,J＝14.8,7.9Hz,1H),3.14(dd,J＝14.8,6.8Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ172.0,155.2,154.7,140.4,138.7,134.8,128.8,128.6,128.3,127.8,127.2,126.9,126.7,126.1,118.5,103.2,85.1,62.1,52.8,42.4,37.8.HRMS(ESI)[M+Na] + calcd for C 27 H 25 NO 5 ,466.1625,found 466.1628.
EXAMPLE 4 preparation of Compound d
The structure of compound d is shown below:
preparation referring to example 1, except that 3-bromophenol was used instead of p-bromophenol, compound d was prepared as a white solid in 80% isolated yield. Of the product 1 The H NMR is shown in FIG. 8, which 13 The C NMR chart is shown in FIG. 9.
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝7.3Hz,2H),7.36(dt,J＝19.8,7.0Hz,3H),7.08(d,J＝8.0Hz,1H),7.05–6.98(m,2H),6.63(dd,J＝8.2,2.0Hz,1H),6.56(d,J＝14.3Hz,1H),4.59(dt,J＝14.3,7.3Hz,1H),4.39(t,J＝8.1Hz,2H),3.74(s,3H),3.65–3.52(m,2H),3.20(dd,J＝14.8,8.0Hz,1H),3.11(dd,J＝14.8,6.8Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ171.5,156.0,155.1,138.1,130.1,128.6,128.4,127.3,126.1,125.0,122.4,122.0,116.6,102.8,85.5,62.1,52.8,42.4,38.4.HRMS(ESI)[M+Na] + calcd for C 21 H 20 NO 5 Br,468.0417,found 468.0417.
EXAMPLE 5 preparation of Compound e
The structure of compound e is shown below:
the procedure is as in example 1 except that instead of p-bromophenol, 5,6,7,8-tetrahydronaphthol was used to prepare compound e as a colorless oil in 69% isolated yield. Of the product 1 The H NMR is shown in FIG. 10, which 13 The C NMR chart is shown in FIG. 11.
1 H NMR(500MHz,CDCl 3 )δ7.56(d,J＝7.7Hz,2H),7.36(t,J＝7.6Hz,2H),7.30(t,J＝7.1Hz,1H),6.84(d,J＝8.3Hz,1H),6.53(d,J＝2.2Hz,1H),6.48(dd,J＝8.2,5.7Hz,2H),4.53(dt,J＝14.5,7.3Hz,1H),4.34(t,J＝8.2Hz,2H),3.70(s,3H),3.59–3.46(m,2H),3.22(dd,J＝14.8,7.8Hz,1H),3.09(dd,J＝14.8,6.9Hz,1H),2.65(s,4H),1.76–1.69(m,4H). 13 C NMR(126MHz,CDCl 3 )δ172.4,155.2,152.5,139.1,138.1,130.7,129.5,128.4,128.1,126.9,126.0,118.7,115.5,103.5,84.6,62.1,52.7,42.4,36.9,29.6,28.6,23.3,23.0.HRMS(ESI)[M+Na] + calcd for C 25 H 27 NO 5 ,444.1781,found 444.1780.
EXAMPLE 6 preparation of Compound f
The structure of compound f is shown below:
the preparation process was conducted in accordance with example 1 except that 4-iodophenol was used in place of p-bromophenol to obtain compound f as a white solid in an isolated yield of 70%. Of the product 1 The HNMR diagram is shown in FIG. 12, which 13 The C NMR chart is shown in FIG. 13.
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝7.8Hz,2H),7.46(d,J＝8.5Hz,2H),7.36(dt,J＝14.1,6.8Hz,3H),6.58(d,J＝14.5Hz,1H),6.54(d,J＝8.6Hz,2H),4.59(dt,J＝14.5,7.4Hz,1H),4.39(t,J＝8.1Hz,2H),3.74(s,3H),3.66–3.52(m,2H),3.18(dd,J＝14.7,8.0Hz,1H),3.10(dd,J＝14.7,6.8Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ171.5,155.2,138.1,138.0,128.6,128.3,127.3,126.1,120.4,102.8,85.3,84.4,62.1,52.8,42.4,38.5.HRMS(ESI)[M+Na] + calcd for C 21 H 20 INO 5 ,493.0412,found 493.0411.
EXAMPLE 7 preparation of Compound g
The structure of compound g is shown below:
preparation example 1 was followed, except that 4-bromophenol was used instead of p-bromophenol, to give g of compound as a white solid in an isolated yield of 75%.Of the product 1 The HNMR scheme is shown in FIG. 14, which 13 The C NMR chart is shown in FIG. 15.
1 H NMR(400MHz,CDCl 3 )δ7.49(d,J＝8.5Hz,2H),7.33(d,J＝8.5Hz,2H),7.28(d,J＝9.0Hz,2H),6.62(d,J＝8.8Hz,2H),6.57(d,J＝14.3Hz,1H),4.52(dt,J＝14.5,7.4Hz,1H),4.38(t,J＝8.0Hz,2H),3.71(s,3H),3.63–3.51(m,2H),3.13(dd,J＝14.7,7.9Hz,1H),3.04(dd,J＝14.6,6.8Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ171.3,155.1,154.2,136.7,133.9(d,J＝3.3Hz),128.2(d,J＝8.1Hz),127.8,119.76,115.5(d,J＝21.6Hz),102.3,100.0,84.9,62.1,52.9,42.4,38.8.HRMS(ESI)[M+Na] + calcd for C 21 H 19 NO 5 ClBr,502.0028,found 502.0027.
EXAMPLE 8 preparation of Compound h
The structure of compound h is shown below:
the preparation process was as in example 1, except that 4-fluorophenol was used instead of p-bromophenol, to give compound h as a colorless oil in an isolated yield of 92%. Of the product 1 The HNMR scheme is shown in FIG. 16, which 19 F NMR is shown in FIG. 17, which 13 A C NMR chart is shown in FIG. 18.
1 H NMR(500MHz,CDCl 3 )δ7.52(d,J＝7.7Hz,2H),7.36(t,J＝7.5Hz,2H),7.31(t,J＝7.2Hz,1H),6.85(t,J＝8.6Hz,2H),6.71(dd,J＝9.1,4.3Hz,2H),6.54(d,J＝14.3Hz,1H),4.60(dt,J＝14.5,7.4Hz,1H),4.36(t,J＝8.1Hz,2H),3.71(s,3H),3.62–3.52(m,2H),3.16(dd,J＝14.8,8.0Hz,1H),3.09(dd,J＝14.8,6.7Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ171.9,158.8,156.9,155.2,151.0,151.0,138.4,128.5,128.4,127.2(d,J＝11.5Hz),126.2,120.0(d,J＝2.3Hz),119.9(d,J＝7.0Hz),115.7(d,J＝6.4Hz),115.5(d,J＝4.9Hz),103.1,85.6,62.1,52.8,52.7,42.4,37.7. 19 F NMR(376MHz,CDCl 3 )δ-121.8.HRMS(ESI)[M+Na] + calcd for C 21 H 20 NO 5 F,408.1218,found 408.1224.
EXAMPLE 9 preparation of Compound i
The structure of compound i is shown below:
the preparation was carried out in accordance with example 1, except that 4- (1-naphthyl) phenol was used instead of p-bromophenol, to give compound i as a colorless oil in an isolated yield of 57%. Of the product 1 The H NMR is shown in FIG. 19, which 13 The C NMR chart is shown in FIG. 20.
1 H NMR(500MHz,CDCl 3 )δ7.91(d,J＝8.0Hz,2H),7.85(d,J＝8.2Hz,1H),7.67(d,J＝7.6Hz,2H),7.51(dd,J＝14.1,6.9Hz,2H),7.43(dd,J＝13.6,6.1Hz,4H),7.40–7.37(m,1H),7.35(d,J＝8.3Hz,2H),6.94(d,J＝8.1Hz,2H),6.60(d,J＝14.3Hz,1H),4.70–4.64(m,1H),4.38(t,J＝8.0Hz,2H),3.80(s,3H),3.60(dd,J＝20.5,8.4Hz,2H),3.34(dd,J＝14.4,8.0Hz,1H),3.23(dd,J＝14.8,6.6Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ172.1,155.2,154.5,139.6,138.8,134.3,133.8,131.7,131.2,130.8,128.6,128.3,127.5,127.2,127.2,126.1,126.0,125.8,125.4,118.1,114.6,103.2,85.1,62.1,52.9,42.4,37.7.HRMS(ESI)[M+Na] + calcd for C 31 H 27 NO 5 ,516.1781,found 516.1782.
EXAMPLE 10 preparation of Compound j
The structure of compound j is shown below:
preparation with reference to example 1, except that p-bromophenol was replaced with 4- (9-anthracenyl) phenol, compound j was prepared as a white solid in an isolated yield of 42%. Of the product 1 The H NMR is shown in FIG. 21, which 13 A schematic C NMR chart is shown in FIG. 22.
1 H NMR(500MHz,CDCl 3 )δ8.49(s,1H),8.05(d,J＝8.5Hz,2H),7.71(d,J＝7.8Hz,2H),7.67(d,J＝8.8Hz,2H),7.47(t,J＝7.5Hz,4H),7.39(dd,J＝14.4,6.7Hz,3H),7.27(d,J＝8.9Hz,2H),7.04(t,J＝12.5Hz,2H),6.64(d,J＝14.3Hz,1H),4.71(dt,J＝14.5,7.4Hz,1H),4.41(t,J＝8.1Hz,2H),3.84(s,3H),3.65(tt,J＝17.0,8.6Hz,2H),3.40(dd,J＝14.9,8.0Hz,1H),3.28(dd,J＝14.9,6.7Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ172.2,155.2,154.6,138.8,136.4,132.2,132.0,131.4,130.4,128.62,128.3,127.3,126.8,126.5,126.2,125.4,125.1,118.4,103.2,85.2,62.1,52.9,42.5,37.7.HRMS(ESI)[M+Na] + calcd for C 35 H 29 NO 5 ,566.1938,found 566.1938.
EXAMPLE 11 preparation of Compound k
The structure of compound k is shown below:
the preparation process was as in example 1 except that 2-naphthol was used instead of p-bromophenol to prepare compound k as a colorless oil with an isolated yield of 42%. Of the product 1 The H NMR is shown in FIG. 23, which 13 A schematic C NMR chart is shown in FIG. 24.
1 H NMR(400MHz,CDCl 3 )δ7.72(t,J＝9.0Hz,2H),7.62(d,J＝7.4Hz,2H),7.57(d,J＝8.1Hz,1H),7.41–7.31(m,5H),7.15(dd,J＝9.0,2.6Hz,1H),6.95(d,J＝2.4Hz,1H),6.52(d,J＝14.3Hz,1H),4.57(dt,J＝14.6,7.4Hz,1H),4.34(dd,J＝10.6,5.7Hz,2H),3.71(s,3H),3.54(dd,J＝16.3,7.9Hz,2H),3.33(dd,J＝15.1,7.8Hz,1H),3.18(dd,J＝15.2,6.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ172.1,155.1,152.9,138.6,134.0,129.4,128.5,128.2,127.5,127.2,127.0,126.3,126.1,124.3,120.3,112.5,103.2,85.2,62.1,52.8,37.7.HRMS(ESI)[M+Na] + calcd for C 25 H 23 NO 5 ,440.1468,found 440.1468.
EXAMPLE 12 preparation of Compound l
The structure of compound i is shown below:
preparation with reference to example 1, except that 3,5-dimethyl-4-bromophenol was used instead of p-bromophenol, compound i was prepared as a colorless oil in 42% isolated yield. Of the product 1 The H NMR is shown in FIG. 25, which 13 A schematic diagram of C NMR is shown in FIG. 26.
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝7.3Hz,2H),7.34(ddd,J＝11.0,9.5,5.7Hz,3H),6.55(d,J＝11.0Hz,3H),4.56(dt,J＝14.5,7.4Hz,1H),4.36(t,J＝8.1Hz,2H),3.72(s,3H),3.64–3.50(m,2H),3.21(dd,J＝14.8,7.9Hz,1H),3.11(dd,J＝14.8,6.8Hz,1H),2.30(s,6H). 13 C NMR(101MHz,CDCl 3 )δ171.9,155.2,153.6,138.9,138.5,128.5,128.3,127.2,126.0,119.7,118.0,103.1,85.0,62.1,52.8,42.4,37.8,24.1.HRMS(ESI)[M+Na] + calcd for C 23 H 24 NO 5 Br,496.0730,found 496.0730.
Example 13 Activity test
The products from the examples were dissolved in DMSO and further diluted in culture medium. The final concentration of DMSO is not more than 0.1% (v/v).
The test cells were human gastric cancer AGS cells, inoculated in a medium containing 10% serum, 1% solution of penicillin-streptomycin, incubated at 37 ℃ and 5% CO 2 In the incubator, the cells were passaged every 2 days, and cells in the logarithmic growth phase were taken out for the experiment.
The IC50 value is determined by a CCK8 method, and the specific process is as follows: taking cells in logarithmic growth phase, and adjusting cell suspension to 7 x 10 with prepared fresh culture medium 3 Per mL to 96 well plates, 150. Mu.L per well volume, 5% CO 2 Incubating at 37 deg.C for 24hrs, adding 10 μ L of the product obtained in examples 1-12 at a concentration of 20, 10,5,2.5,1.25,0.625 μ M, respectively, incubating, and 96hAdding 10. Mu.L of CCK8, respectively, and subjecting to 37 ℃ and 5% CO 2 After 1hr in the incubator, absorbance at 450nm was measured with a multifunctional microplate reader (FLUOstar Promega).
A Control group and a blank group are simultaneously arranged, wherein the Control group contains AGS cells and DMSO but no compound, and the blank group only contains DMSO and no cells. The results for each experimental condition were averaged over 3 replicate wells in one experiment.
Cell viability (%) = [ a (medicated) -a (blank) ]/[ a (Control group) -a (blank) ] × 100, inhibition = 1-cell viability (%).
For each sample, the average cell growth was expressed as a percentage of the average Control cell growth, and the IC50 (the concentration of drug required to reduce cell growth to 50% of the Control group) was calculated using GraphPad prism 7.
The measurement results are shown in Table 1.
IC of Compounds of Table 1 for inhibition of AGS cell proliferation 50 Value of
| Serial number | Compound numbering | IC 50 Value/. Mu.M |
| 1 | a | 9.21 |
| 2 | b | 8.89 |
| 3 | c | 5.49 |
| 4 | d | 12.22 |
| 5 | e | 11.52 |
| 6 | f | 12.56 |
| 7 | g | 8.42 |
| 8 | h | 8.55 |
| 9 | i | 9.21 |
| 10 | j | 8.56 |
| 11 | k | 12.55 |
| 12 | l | 15.22 |
As can be seen from table 1, it is,the 12 compounds all have good inhibition effect on AGS cells, and the IC of the compounds 50 All values are below 16. Mu.M, where the IC of compounds a, b, c, g, h and i 50 Values below 10. Mu.M, which are the best inhibitors of AGS cells, are compound c, its IC 50 The value was 5.49. Mu.M. The results show that the compound prepared by the invention can be developed and prepared into a medicine for treating gastric cancer.
Further investigation was conducted with compound c having the best inhibitory effect as the object of investigation by arranging compound c in a plurality of concentration gradients and testing the inhibitory activity against AGS cells at different concentrations by referring to the above-mentioned method, and the results of the test are shown in FIG. 27, from which it is clear that IC of compound c is shown 50 The value was 5.49. Mu.M.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (7)
1. A carboxylic ester derivative containing aryl ether substituted oxazolidinone is characterized in that the structure of the compound is shown as the formula (I):
wherein Ar is 1 Is phenyl, 3-bromophenyl, 4-fluorophenyl, 4-iodophenyl, 3,5-dimethyl-4-bromophenyl, p-biphenylyl, 2-naphthyl, 4- (9-anthryl) phenyl, 4- (1-naphthyl) phenyl, 5,6,7,8-tetrahydronaphthyl;
Ar 2 is phenyl or 4-chlorophenyl.
2. The method of claim 1The aryl ether substituted oxazolidinone carboxylic ester derivative is characterized in that Ar is 1 Is phenyl, 4-bromophenyl, 4-fluorophenyl, p-biphenyl, 2-naphthyl, 4- (9-anthryl) phenyl; ar (Ar) 2 Is phenyl or 4-chlorophenyl.
3. A process for preparing carboxylic ester derivatives containing aryl ether substituted oxazolidinones as claimed in claim 1 or 2, wherein Ar is Ar 1 -OH、
Using (acetonitrile) [ (2-biphenyl) di-tert-butylphosphine as raw material and molecular sieve as water absorbent]Using hexafluoroantimonate gold (I) as a catalyst, firstly, ar 1 Dissolving OH, a water absorbent and a catalyst in dichloromethane to prepare a solution A,
mixing and dissolving the mixture in dichloromethane to prepare a solution B, and then dropwise adding the solution B into the solution A for reaction to obtain a target product;
wherein, ar is 1 And Ar 2 Is defined in accordance with claim 1 or 2.
4. The method of claim 3, wherein Ar is Ar during the reaction 1 -OH、
And the molar ratio of the reaction with the catalyst is 1.0-1.5.
5. The method of claim 3, wherein Ar is Ar for the preparation of carboxylic acid ester derivatives of aryl ether substituted oxazolidinones 1 The dosage of the water absorbent is 50.0mg/mmol based on the dosage of OH, and the dosage of dichloromethane is 0.5 mL-1.0 mL/mmol.
6. The method for preparing carboxylic ester derivatives containing aryl ether substituted oxazolidinones as claimed in claim 3, wherein the reaction temperature is-40 ℃ to 40 ℃; the reaction time is 0.5 to 3.0 hours.
7. The use of carboxylic ester derivatives containing aryl ether substituted oxazolidinones as claimed in claim 1 or 2 for the preparation of anti-cancer drugs, wherein the anti-cancer drugs are drugs for inhibiting gastric cancer.
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