CN112661657B - Sertraline side chain amino structure derivative and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a sertraline side chain amino structure derivative, the structural formula is shown as a formula I or a formula II, wherein R 1 Is H or cyclopropane, R 2 Selected from alkyl groups,Naphthyl, alkylamine, cyclopropane, phenyl, or phenyl substituted in position 3 and/or 4 with alkyl, methoxyalkyl, haloalkyl, halo; r is R 3 Is hydrogen or 1-haloalkyl. The invention also provides a preparation method of the sertraline derivative and application of the sertraline derivative in preparation of medicines for treating gastric cancer. The sertraline derivative provided by the invention has obvious sensitization effect on drug-resistant gastric cancer cells.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to derivatives of sertraline side chain amino structures, and a preparation method and application thereof.
Background
Sertraline is a selective serotonin reuptake inhibitor, and in addition to the application in depression, the report on the application value in tumor treatment has been increased significantly in recent years. For example, sertraline has been reported to induce ER calcium release in human prostate cancer cells PC 3. In addition, sertraline interacts with and reduces cellular levels of translation-controlled tumor proteins, resulting in reduced migration characteristics and colony forming ability of melanoma cells. The role of sertraline in the treatment of non-small cell lung cancer (NSCLC) was determined in 2018 by the group of Xiufeng Pang subjects in "reuse of sertraline to sensitize non-small cell lung cancer cells to erlotinib by induction of autophagy", demonstrating that sertraline inhibits the viability of NSCLC cells, showing synergy of erlotinib. They have further studied their mechanism and demonstrate that sertraline enhances the therapeutic effect of erlotinib in NSCLC cells by targeting the AMPK/mTOR signaling pathway. The VelteDrinberg group demonstrates that sertraline in combination with nanomedicines can regulate multi-drug resistance in cancer.
According to global cancer statistics published by the american cancer society in 2019, gastric cancer has a high incidence (5.7% of new cancers, fifth) and mortality (8.2% of cancer-induced deaths, third) worldwide. The treatment modalities for gastric cancer generally include surgery, chemotherapy, or targeted drug therapy. However, conventional therapeutic means have difficulty in achieving satisfactory results due to low response rate, very high susceptibility to drug resistance, and the like. Therefore, the development of a more effective novel anti-gastric cancer drug has important significance for improving the cure rate of gastric cancer and prolonging the life cycle of patients. The development of new anti-gastric cancer drugs mainly needs to solve the key problem of tumor drug resistance.
Disclosure of Invention
The invention aims to provide a sertraline derivative prepared by modifying a sertraline side chain, and the sertraline derivative has a sensitization effect when being used for drug-resistant gastric cancer cells, so as to solve the problem that tumor cells have drug resistance to chemotherapeutic drugs in the current gastric cancer treatment.
The invention firstly provides a sertraline side chain amino structure derivative, the structural formula is shown as a formula I or a formula II,
wherein R is 1 Is H or cyclopropane, R 2 Selected from alkyl groups, Naphthyl, alkylamine, cyclopropane, phenyl, or phenyl substituted in position 3 and/or 4 with alkyl, methoxyalkyl, haloalkyl, halo; r is R 3 Is hydrogen or 1-haloalkyl.
In accordance with the present inventionIn one embodiment of the invention, R is the structural formula of a sertraline side chain amino structure derivative of formula I 2 Is a straight chain alkyl or a branched alkyl.
In one embodiment according to the invention, when the sertraline derivative has the formula I, R 2 Selected from- (CH) 2 )nCH 3 N=1, 2 or 4, -CH (CH) 3 ) m, m=2, 3, 4, 5, 6 … and the like are integers greater than or equal to 2, or- (CH) 2 )xC 6 H 5 X=0, 1, 2, 3 …, etc.
The invention also provides a preparation method of the sertraline side chain amino structure derivative, which comprises the following steps:
1) Dissolving a first intermediate compound in an organic solvent, adding a modifying group compound and tetraisopropyl titanate in an inert atmosphere, and reacting at 70-100 ℃;
2) Step 1), adding sodium cyanoborohydride after full reaction, and reacting at 70-100 ℃;
3) After the reaction of the step 2) is completed, adding a quenching agent for quenching;
4) Extracting, removing water and purifying by chromatography to obtain a first product, wherein the first product is a sertraline derivative shown in a structural formula I;
wherein the equivalent ratio of the first intermediate compound to the modifying group compound, tetraisopropyl titanate and sodium cyanoborohydride is 1: 2-1: 3.375-1: 2.5;
the structural formula of the first intermediate is shown in a formula III,
the structural general formula of the modification group is shown as a formula V,
wherein R is 1 Is H or cyclopropane, R 2 Selected from alkyl groups, Naphthyl, alkylamine, cyclopropane, phenyl, or phenyl substituted in position 3 and/or 4 with alkyl, methoxyalkyl, haloalkyl, halo.
In one embodiment according to the present invention, further comprising: the preparation method of the sertraline side chain amino derivative with the structural general formula II comprises the following specific steps:
5) Weighing a proper amount of a second intermediate compound, mixing the second intermediate compound with a proper amount of dichloromethane in a container protected by inert atmosphere, adding triethylamine after ice bath to 0 ℃, stirring and uniformly mixing, then dropwise adding a compound with a structural formula VI, stirring at room temperature until the reaction is complete, quenching with a quencher, extracting with an extractant, and purifying by column chromatography to obtain a compound with a formula II; wherein the structural formula of the second intermediate compound is formula IV, and R is 3 Is hydrogen or 1-haloalkyl;
preferably, the molar ratio of the second intermediate compound, triethylamine, compound of formula vi is 1:2:1.5.
in one embodiment according to the invention, the organic solvent in step 1) is isopropanol or methanol.
In one embodiment according to the invention, the quencher is saturated sodium bicarbonate solution, saturated sodium bicarbonate or saturated ammonium chloride.
In one embodiment according to the invention, the extractant is methylene chloride.
In one embodiment according to the invention, the column chromatography She Xituo liquid is present in a volume ratio of 10-20:1 or the volume ratio of petroleum ether to ethyl acetate is 1:100 dichloromethane and triethylamine.
In one embodiment according to the invention, the first intermediate compound in step 1) is prepared by a process comprising the steps of:
mixing the compound 1 with aluminum trichloride, adding the compound 2 under an inert atmosphere, heating to 100 ℃ for reaction, cooling to room temperature after the reaction is completed, quenching by using a mixture of 1N hydrochloric acid and ice, extracting, removing water, spin-drying, and then performing column chromatography separation to obtain a first intermediate compound;
wherein the structural formula of the compound 1 isCompound 2 has the formula->
In one embodiment according to the invention, the second intermediate is achieved by a process comprising the steps of:
mixing a proper amount of first intermediate compound with ammonium acetate, adding a proper amount of isopropanol in an inert atmosphere, fully reacting at 70-100 ℃, then adding sodium borohydride for continuous reaction, cooling to room temperature, quenching with a quenching agent, extracting with an extracting agent, and purifying by column chromatography to obtain a second intermediate compound; preferably, the molar ratio of the first intermediate compound to ammonium acetate is 1:2;
the invention further provides application of the sertraline derivative in preparing medicines for treating gastric cancer.
The synthetic derivatives of the sertraline structure in the invention are original and not reported in the literature;
compared with the prior art, the derivatives with the sertraline structure synthesized in the invention, wherein part of compounds can sensitize drug-resistant gastric cancer cells, and the invention has the following characteristics:
the sertraline derivative provided by the invention has an obvious sensitization effect on gastric cancer cells, and can be used for sensitization of drug-resistant gastric cancer cells or for improving the inhibition effect of chemotherapy drugs on tumor cells.
Drawings
FIG. 1 is a schematic representation of the synthetic route to sertraline side chain amino structure derivatives of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of compound 5 a;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of compound 6 a;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of compound 5 k;
FIG. 5 is a graph showing the proliferation test results of the human gastric cancer cell-resistant strain SGC-7901/DDP inhibiting compound 6 a;
FIG. 6 is a graph of experimental results of the proliferation of human gastric cancer cell-resistant strain SGC-7901/DDP inhibition of compound 6 b;
FIG. 7 is a graph of experimental results of the proliferation of human gastric cancer cell-resistant strain SGC-7901/DDP inhibited by compound 6 c;
FIG. 8 is a graph showing the results of experiments on the proliferation of human gastric cancer cell-resistant strains SGC-7901/DDP with compounds 5t and 6 d.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Unless otherwise specified, all reagents used in this example were analytically pure and all chemical reaction progress was measured by thin layer chromatography.
Example 1: synthesis of Compounds
The synthetic scheme of the sertraline side chain amino structure derivative is shown in the figure 1, and compound 1 and aluminum trichloride are weighed into a three-neck flask and are mixed in N 2 Adding the compound 2 into the mixture under the protection condition, heating to 100 ℃ for reaction for 2.5 hours, cooling to room temperature after the reaction is completed, quenching by using a mixture of 1N hydrochloric acid and ice, extracting by using dichloromethane, performing conventional water removal operation, performing column chromatography separation after spin drying to obtain an intermediate compound; the equivalent ratio of the compound 1 to the aluminum trichloride to the compound 2 is as follows: 1:8.157 ～ 1：1：2.5。
1. Process for the synthesis of sertraline derivatives of formula (I)
Dissolving intermediate compound III in isopropanol solution, N 2 Adding a modifying group compound and tetraisopropyl titanate into the solution under the protection condition, reacting for two hours at 85 ℃, adding sodium cyanoborohydride into the solution, reacting at 85 ℃, quenching the solution with saturated sodium bicarbonate solution after the reaction is completed, extracting the solution with two paths of methane, performing conventional water removal operation, performing spin-drying, and performing column chromatography separation to obtain the sertraline derivative with the structural formula shown in the formula I; the equivalent ratio of the intermediate compound to the modifying group compound, tetraisopropyl titanate and sodium cyanoborohydride is 1:2 ～ 1：3.375 ～ 1。
The structural formula of the modifying group is shown in a formula V.
Wherein R is 1 Is H or cyclopropane, R 2 Selected from alkyl groups, Naphthyl, alkylamine, cyclopropane, phenyl, or phenyl substituted in position 3 and/or 4 with alkyl, methoxyalkyl, haloalkyl, halo.
2. Synthesis procedure for Sertraline derivatives of formula II
After obtaining intermediate compound III, the sertraline compound derivative of formula II may be further synthesized as shown in FIG. 1.
Intermediate compound III (583.9 mg (2 mmol)) and compound ammonium acetate (311.4 mg (4 mmol)) were weighed out, vented in a three-necked flask and purged with N 2 Protecting, adding an appropriate amount of isopropanol, heating to 80 ℃ for reaction for 2 hours, adding a compound sodium borohydride (756.6 mg (20 mmol)) into the mixture, reacting for 16 hours at 80 ℃, cooling to room temperature, quenching the mixture with saturated sodium bicarbonate solution, extracting the mixture with dichloromethane, drying the mixture, spin-drying the mixture, separating the mixture by column chromatography with an eluent of PE: EA=20:1, and spin-drying the mixture to obtain an intermediate compound IV.
Intermediate compound iv (200 mg (0.68 mmol)) was weighed out, purged in a flask and protected with nitrogen and an appropriate amount of dichloromethane was added. Triethylamine (137.7 mg (1.36 mmol)) is added thereto after ice bath to 0 ℃ and stirring is carried out for 5 minutes, then a compound (1.03 mmol) with the structural formula VI is added thereto dropwise, and stirring is carried out at room temperature until the reaction is completed, then the solution is quenched by saturated sodium bicarbonate solution, extracted by dichloromethane, dried by anhydrous sodium sulfate and separated by spin-dry column chromatography to obtain the sertraline side chain amino derivative with the structural formula II.
The list of partial sertraline derivatives synthesized in the present invention is shown in Table 1:
TABLE 1 Sertraline derivatives display Table prepared by the invention
EXAMPLE 2 Synthesis of Sertraline derivatives No.1
The intermediate compound III (583.9 mg (2 mmol)) was weighed into a dry three-necked round bottom flask equipped with a stirrer, subjected to anhydrous anaerobic treatment, n-propylamine (0.33 ml (4 mmol)) was added thereto, stirred for 5 minutes, tetraisopropyl titanate (2 ml (6.75 mmol)) was added thereto, refluxed in an oil bath at 85℃for 2 hours, cooled to room temperature after 2 hours, and sodium cyanoborohydride (314.2 mg (5 mmol)) was added thereto and heated to 85℃to reflux until the reaction was completed. Cooling the reaction liquid to room temperature after the reaction is completed, adding a proper amount of saturated sodium bicarbonate solution into the reaction liquid for quenching, extracting the reaction liquid with dichloromethane, drying the reaction liquid with anhydrous sodium sulfate, carrying out suction filtration and spin-drying to obtain yellow oily matter; and then, column chromatography is carried out to separate the eluent from petroleum ether: ethyl acetate=20:1, the eluent was collected and concentrated to dryness to give the product as a colourless oil in 47% yield.
Compound 5a structural formula was determined using 600MHz nuclear magnetic hydrogen spectroscopy and high resolution: 1 H NMR(600MHz,CDCl3),δ7.31(d,J＝7.5Hz, 1 H),7.27(d,J＝8.2Hz, 1 H),7.19(d,J＝2.1Hz, 1 H),7.13(t,J＝7.4Hz, 1 H),7.03(t,J＝7.5Hz, 1 H),6.92(dd,J＝8.2,1.5Hz, 1 H),6.72(d,J＝7.7Hz, 1 H),3.91(dd,J＝9.0,5.7Hz, 1 H),3.76(s, 1 H),2.69–2.57(m, 2 H),2.08–1.99(m, 1 H),1.96–1.88(m, 2 H),1.80–1.72(m, 1 H),1.50(dq,J＝14.2,7.1Hz, 2 H),0.89(t,J＝7.4Hz, 3 H)；HRMS(ESI+):m/z[M+H]+calcd for C 19 H 22 Cl 2 N:334.1124,found 334.1124.
EXAMPLE 3 Synthesis of Sertraline derivative No.22
Intermediate compound iii (583.9 mg (2 mmol)) was weighed into a dry three-necked round bottom flask with a stirrer, subjected to anhydrous anaerobic treatment, added with Boc-protected ethylenediamine (0.65 ml (4 mmol)) and stirred for 5 minutes, added with tetraisopropyl titanate (2 ml (6.75 mmol)) and refluxed in an oil bath at 85 ℃ for 2 hours, cooled to room temperature after 2 hours, added with sodium cyanoborohydride (314.2 mg (5 mmol)) and warmed to 85 ℃ and refluxed until the reaction was complete. Cooling the reaction liquid to room temperature after the reaction is completed, adding a proper amount of saturated sodium bicarbonate solution into the reaction liquid for quenching, extracting the reaction liquid with dichloromethane, drying the reaction liquid with anhydrous sodium sulfate, carrying out suction filtration and spin-drying to obtain yellow oily matter; then separating by column chromatography, wherein the eluent is petroleum ether with the volume ratio of 10:1: ethyl acetate, collecting eluent, concentrating to obtain a colorless oil, weighing the colorless oil in a flask with a stirrer, adding a proper amount of trifluoroacetic acid and dichloromethane, and adding the trifluoroacetic acid: dichloromethane=1:5, stirring at normal temperature for 3.5 hours, quenching with saturated sodium bicarbonate solution after the reaction is complete, extracting with dichloromethane, drying with anhydrous sodium sulfate, suction-filtering, spin-drying, and separating by column chromatography, wherein the eluent is dichloromethane: triethylamine=100:1, collecting the eluent, concentrating to dryness to obtain the product with a colorless oily product yield of 83%;
the structural formula of the compound (code 6 a) is determined by using a 600MHz nuclear magnetic hydrogen spectrum and high resolution: 1 H NMR(600MHz,CDCl 3 )δ7.39(d,J＝7.7Hz, 1 H),7.32(d,J＝8.2Hz, 1 H),7.24(s, 1 H),7.18(t,J＝7.4Hz, 1 H),7.08(t,J＝7.4Hz, 1 H),6.96(d,J＝8.2Hz, 1 H),6.78(d,J＝7.7Hz, 1 H),4.01–3.94(m, 1 H),3.81(d,J＝4.0Hz, 1 H),2.91–2.77(m, 4 H),2.06(dd,J＝21.2,10.1Hz, 1 H),2.02–1.91(m, 2 H),1.81(dd,J＝17.1,7.4Hz, 1 H)；HRMS(ESI + ):m/z[M+H] + calcd for C 18 H 21 Cl 2 N 2 :335.1076,found 335.1083.
the chemical reaction equation is as follows:
EXAMPLE 4 Synthesis of Sertraline derivative No.11
The intermediate compound III (583.9 mg (2 mmol)) was weighed into a dry three-necked round bottom flask equipped with a stirrer, subjected to anhydrous anaerobic treatment, added thereto p-methoxybenzylamine (0.52 ml (4 mmol)) and stirred for 5 minutes, added thereto tetraisopropyl titanate (2 ml (6.75 mmol)) and refluxed in an oil bath at 85℃for 2 hours, cooled to room temperature after 2 hours, added thereto sodium cyanoborohydride (314.2 mg (5 mmol)) and warmed to 85℃and refluxed until the reaction was completed. Cooling the reaction liquid to room temperature after the reaction is completed, adding a proper amount of saturated sodium carbonate solution into the reaction liquid for quenching, extracting with dichloromethane, drying with anhydrous sodium sulfate, carrying out suction filtration and spin-drying to obtain yellow oily matter; and then, column chromatography is carried out to separate the eluent from petroleum ether: ethyl acetate=20:1, the eluent was collected and concentrated to dryness to give the product as a colourless oil in 27% yield;
compound (code 5 k) structural formula was determined using 600MHz nuclear magnetic hydrogen spectroscopy and high resolution: 1 H NMR(600MHz,CDCl 3 )δ7.34(dd,J＝16.1,6.8Hz, 4 H),7.29(s, 1 H),7.19(t,J＝7.4Hz, 1 H),7.11(t,J＝7.4Hz, 1 H),7.01(d,J＝8.2Hz, 1 H),6.91(d,J＝8.2Hz, 2 H),6.80(d,J＝7.7Hz, 1 H),4.00(dd,J＝8.6,5.0Hz, 1 H),3.93(d,J＝13.0Hz, 1 H),3.87(s, 1 H),3.81(d,J＝12.3Hz, 4 H),2.18(dd,J＝20.7,11.2Hz, 1 H),2.06–1.99(m, 2 H),1.85(td,J＝11.5,4.2Hz, 1 H)；HRMS(ESI + ):m/z[M+H] + calcd for C 24 H 24 Cl 2 NO:412.1229,found412.1234.
the chemical reaction equation is as follows:
EXAMPLE 5 proliferation experiments of human gastric cancer cell-resistant Strain SGC-7901/DDP inhibition
(1) Cell collection
A. Gastric cancer cell resistant strain SGC-7901/DDP (purchased from American Type Culture Collection (ATCC)) was cultured in complete medium (RPMI-1640 medium containing 10% by volume of fetal bovine serum and 1% by volume of green chain double antibody) at 37℃with 5% CO 2 After culturing for 48 hours under the condition, observing the growth state of the cells by a microscope, and when the melting degree of the cells reaches 80-90 percentThen taking out from the incubator;
B. removing the culture medium by vacuum pump, washing the cells once by using PBS buffer solution, sucking out the PBS, adding 1mL pancreatin digestive juice preheated to room temperature into a culture dish, and digesting for 2 minutes by using a incubator at 37 ℃;
C. adding 5mL of complete culture medium preheated to 37 ℃ to stop digestion, and repeatedly and gently blowing the bottom of the culture dish by a pipetting gun to make cells fall off to form cell suspension;
D. the cell suspension was transferred to a 15mL centrifuge tube, centrifuged at 800rpm for 5min with a low speed centrifuge, the supernatant was removed, and 10mL of complete medium was added to resuspend the cells.
(2) Cell plating
A. Taking one 96-well plate, adding 100 mu L of PBS buffer solution into 36 wells around, and adding 90 mu L of the cell suspension into 60 wells in the center, wherein the number of cells in each well is 5000 cells/well;
B. the 96-well plate inoculated with the cells was returned to the 37℃incubator for further culture overnight to allow the cells to adhere.
(3) Dosing treatment
A. The compounds No.22, 23, 24 and 25 are respectively precisely weighed, and then prepared into 50mmol of medicine mother liquor by dimethyl sulfoxide (DMSO), and diluted into 10, 20, 40, 80, 120, 160, 200 and 240 mu mol/L of serial concentration gradient medicine liquor by complete culture medium (RPMI-1640 culture medium containing 10% of fetal bovine serum and 1% of green chain diabase);
B. adding the diluted liquid medicine into corresponding cell inoculation holes according to the dosage of 10 mu L/hole, setting 3 compound holes (the final concentration of the compound in each hole is 1, 2, 4, 8, 12, 16, 20 and 24 mu mol/L) at each concentration, and setting a negative control hole (adding a dimethyl sulfoxide complete culture medium solution with the volume fraction of 0.1 percent) and a blank control hole (without cells and liquid medicine);
C. after the medicine is added, the pore plate is fully shaken to ensure that the medicine liquid is fully and evenly mixed, and then the mixture is put back into a 37 ℃ incubator to be continuously cultured for 24 hours.
(4) Cell proliferation activity assay
A. 10. Mu.L of CCK-8 solution (Cell Counting Kit-8, available from Biyun Tian, C0039) was added to each well, and the wells were shaken thoroughly and then returned to the 37℃incubator for further incubation for 2h;
B. taking out the 96-well plate, and reading the OD value of each well at the wavelength of 450nm by using an enzyme-labeled instrument;
C. half inhibition concentrations (IC 50) of each compound were calculated to inhibit proliferation of gastric cancer cell-resistant strain SGC-7901/DDP.
The experimental results are shown in fig. 5-8: the synthesized compounds can exert biological activity of inhibiting proliferation of gastric cancer cell drug-resistant strain SGC-7901/DDP.
The above summary and the detailed description are intended to demonstrate practical applications of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent alterations, or improvements will occur to those skilled in the art, and are within the spirit and principles of the invention. The scope of the invention is defined by the appended claims.
Claims (8)
1. A sertraline side chain amino structure derivative is characterized in that the structural formula is shown in a formula I,
wherein R is 1 Is H, R 2 Selected from the group consisting of-CH 2 NH 2 、-(CH 2 ) 3 NH 2 、-(CH 2 ) 5 NH 2 Any one of them.
2. The process for producing a sertraline side chain amino structure derivative according to claim 1, which comprises:
1) Dissolving a first intermediate compound in an organic solvent, adding a modifying group compound and tetraisopropyl titanate in an inert atmosphere, and reacting at 70-100 ℃;
2) Step 1), adding sodium cyanoborohydride after full reaction, and reacting at 70-100 ℃;
3) After the reaction of the step 2) is completed, adding a quenching agent for quenching;
4) Extracting, removing water, and purifying by column chromatography;
5) Adding trifluoroacetic acid and dichloromethane, reacting at normal temperature, and adding a quenching agent for quenching;
6) Extracting, drying and separating by column chromatography to obtain a first product, wherein the first product is a sertraline side chain amino structure derivative shown in a structural formula I;
the quenching agent adopted in the quenching step is saturated sodium bicarbonate solution; the extractant adopted in the extraction step is dichloromethane;
wherein the equivalent ratio of the first intermediate compound to the modifying group compound, tetraisopropyl titanate and sodium cyanoborohydride is 1: 2-1: 3.375-1: 2.5;
the structural formula of the first intermediate compound is shown as a formula III,
the structural formula of the modifying group is shown as a formula V,
wherein R is 1 Is H, R 2 is-CH 2 NH 2 。
3. The process according to claim 2, wherein the organic solvent in step 1) is selected from isopropanol or methanol.
4. The method of claim 2, wherein the column chromatography eluent in step 4) is in a volume ratio of 10 to 20:1 or the volume ratio of petroleum ether to ethyl acetate is 100:1 dichloromethane and triethylamine.
5. The process according to claim 2, wherein the ratio of trifluoroacetic acid to dichloromethane in step 5) is 1:5.
6. the method of claim 2, wherein the eluent from which the column layer is separated in step 6) is dichloromethane and triethylamine, dichloromethane: the volume ratio of triethylamine is 100:1.
7. the method of claim 2, wherein the first intermediate compound of step 1) is prepared by a process comprising the steps of:
mixing the compound 1 with aluminum trichloride, adding the compound 2 under an inert atmosphere, heating to 100 ℃ for reaction, cooling to room temperature after the reaction is completed, quenching by using a mixture of 1N hydrochloric acid and ice, extracting, removing water, spin-drying, and then performing column chromatography separation to obtain a first intermediate compound;
wherein the structural formula of the compound 1 isCompound 2 has the formula->
8. The use of a sertraline side chain amino structure derivative according to claim 1 for the manufacture of a medicament for the treatment of gastric cancer.
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