CN117229146A - Caffeic acid phenethyl ester derivative and preparation method and application thereof - Google Patents

Caffeic acid phenethyl ester derivative and preparation method and application thereof Download PDF

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CN117229146A
CN117229146A CN202311157744.XA CN202311157744A CN117229146A CN 117229146 A CN117229146 A CN 117229146A CN 202311157744 A CN202311157744 A CN 202311157744A CN 117229146 A CN117229146 A CN 117229146A
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acid
acrylate
naphthylene
dihydroxy
white solid
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吴亮
董昊
杨莎
谢唯佳
张光宇
冯陈杰
高源�
蔡奚云弋
刘玉琳
钱洪发
蒋琪
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China Pharmaceutical University
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Abstract

The invention discloses a derivative of caffeic acid phenethyl ester or pharmaceutically acceptable salts and stereoisomers thereof, and a pharmaceutical composition containing the derivative, wherein the compound has good anti-tumor effect and can effectively inhibit proliferation of tumor cells. The invention also discloses a preparation method of the compound and application of the compound in preparing medicines for preventing and/or treating tumors.

Description

Caffeic acid phenethyl ester derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a caffeic acid phenethyl ester derivative, a preparation method and application thereof.
Background
Diffuse large B-cell lymphoma (Diffuse Large B Cell Lymphoma, DLBCL) is a fast-growing hematological malignancy, one of the most common types in non-hodgkin lymphomas. The annual incidence of DLBCL in adults is about 7-8 per 10 tens of thousands of people. The disease occurs mainly in the elderly, with an average diagnostic age around 70 years, but may also occur at any age.
Epstein barr virus is a virus that is widely present in the human population and primarily targets B lymphocytes, most of which have been infected in puberty and which persists for life, often without causing significant symptoms. However, in some cases, epstein barr virus infection can cause some hematological malignancies, such as non-hodgkin lymphomas, of which EBV positive DLBCL (ebv+dlbcl) is one. EBV-infected B cells lead to latent infection, most of which are eliminated by cytotoxic T cells and NK cells, but some EBV-infected B cells escape by down-regulating antigen expression. They then pass through germinal centers and then exist as EBV-infected memory cells. EBV infected B cells express viral proteins such as LMP1, EBNA2, etc. Wherein LMP1 is a transmembrane protein involved in cell cycle and apoptosis regulation, promoting the growth of virus-invasive B cells. EBNA1 is a nuclear antigen protein that plays a key role in replication and maintenance of stability of viral genomes. EBNA2 is involved in activation of epstein barr virus early and late transcription and plays a role in expression of other genes. The function of these proteins is closely related to the processes of infection, replication and cell transformation of EBV.
The frequency of EBV positive DLBCL in DLCBL is about 2.5-14.0%, and incidence rate of east Asian population is higher. Most cases occur in patients older than 50 years old, with men predominated. Clinical features of ebv+dlbcl include older age, more advanced clinical staging, higher extra-junction involvement, worse physical performance status, etc., compared to EBV-DLBCL.
Ebv+dlbcl is also commonly treated with R-CHOP and consists of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. The response to first line treatment (complete or partial remission) was 72% and 92.3% (p=0.006) for EBV positive and EBV negative patients, respectively, i.e. the response rate to first line treatment was significantly reduced for EBV positive DLBCL patients. The 5 year OS and PFS rates for EBV+DLBCL patients were 58.9% and 48.6%, respectively, and the EBV+DLBCL patients had poorer OS and PFS than the EBV negative patients. Thus, there is a great clinical need for new drugs or pharmaceutical compositions that are effective in the treatment of ebv+dlbcl and DLBCL.
Caffeic Acid Phenethyl Ester (CAPE) is a natural product commonly found in plant propolis, and has the following structural formula:
the chemical structure of the caffeic acid is phenethyl diester type caffeic acid. CAPE has various biological activities and is widely used in the fields of medicines, foods, cosmetics and the like. Studies show that CAPE has various biological activities such as oxidation resistance, inflammation resistance, bacteria resistance, virus resistance, tumor resistance and the like, and also has the effects of regulating an immune system, reducing cholesterol, inhibiting platelet aggregation, promoting skin repair and the like. In recent years, the antitumor effect of CAPE has been extensively focused and studied. Experiments prove that CAPE can induce apoptosis of tumor cells, inhibit proliferation of the tumor cells, and prevent invasion and metastasis of the tumor cells. In addition, CAPE can also enhance the activity of immune cells, enhance the immunity of the body, and reduce the side effects of radiotherapy and chemotherapy.
Therefore, the development of the caffeic acid phenethyl ester derivatives has important significance for researching new drugs or pharmaceutical compositions for treating the EBV+DLBCL and the DLBCL.
Disclosure of Invention
The invention aims to: the invention aims to provide a (E) -3- (5, 6-dihydroxy-2-naphthylene) acrylic ester compound shown in a general formula I or pharmaceutically acceptable salt and stereoisomer thereof:
wherein,
r is selected from the group consisting of-H, -F, -Cl, -Br, -I, -CF 3 ，-CCl 3 ，-NO 2 ，-COCH 3 ，-OCOCH 3 ，-CH 3 ，-OCH 3 ，-OC 2 H 5 ，-NH 2 ，-NHSO 2 CH 3 ，-SO 2 NH 2 Or NHCOCH 3 ；
n=1, 2,3, 4 or 5.
In some preferred embodiments, the pharmaceutically acceptable salts include acid addition salts of compounds of formula I with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; also included are the acid salts of the compounds of formula I with inorganic bases.
In some more preferred embodiments, the pharmaceutically acceptable salts include basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.
The compounds of the general formula I according to the invention are preferably the following compounds: (E) Phenyl ethyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl propyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl butyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl pentyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl hexyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylethyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylpropyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylbutyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylpentyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylhexyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate.
The compounds of the general formula I according to the invention are furthermore preferably the following compounds:
the compounds of the general formula I according to the invention mentioned above may also be present in the form of their salts, which are converted in vivo into compounds of the general formula I. For example, within the scope of the present invention, the compounds of the present invention are converted to pharmaceutically acceptable salt forms and used in salt form according to procedures known in the art.
All tautomeric forms of the compounds of formula I of the invention are included within the scope of the invention. The compounds of the invention may exist in specific geometric or stereoisomeric forms. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the scope of the present invention.
It is another object of the present invention to provide a process for the preparation of a compound having the general formula I comprising the steps of:
(1) Uniformly dispersing 6-bromo-2-naphthol, 1, 3-bis (diphenylphosphine) propane and palladium acetate in DMF, sequentially adding triethylamine and ethyl acrylate, heating and reacting at 115 ℃ under the protection of argon for overnight, and performing post-treatment to obtain a crude product, and performing silica gel column chromatography on the crude product to obtain a white solid;
(2) Dissolving the solid in ethanol, adding potassium hydroxide, stirring thoroughly, and reacting completely to obtain white solid;
(3) Dissolving the white solid in tetrahydrofuran for standby, dissolving an alcohol fragment and triphenylphosphine in tetrahydrofuran, adding diisopropyl azodicarboxylate into tetrahydrofuran solution of phenethyl alcohol and triphenylphosphine under ice bath condition, fully stirring, adding the initially prepared tetrahydrofuran solution into a reaction system in ice bath, moving the system to room temperature, fully stirring, post-treating to obtain a crude product, and carrying out silica gel column chromatography on the crude product to obtain the white solid;
(4) Dissolving the white solid in DMSO in the last step, adding 2-iodoxybenzoic acid into a reaction system, fully stirring, changing the reaction system from colorless to yellow, finally changing the reaction system into orange-red, and carrying out post treatment to obtain an orange-red solid;
(5) And (3) dissolving the orange-red solid in acetonitrile, adding an aqueous solution of sodium dithionite into the acetonitrile solution, fully stirring under the protection of argon, changing the reaction system from orange-red to pale yellow, performing post-treatment to obtain a crude product, and separating the crude product by column chromatography to obtain a white solid which is the target compound.
The compounds of the general formula I can be prepared by the preparation method or the preparation method similar to the preparation method, and corresponding starting materials are selected according to different substituents. Those skilled in the art will recognize that the above routes are helpful in understanding the present invention, but do not limit the invention unless otherwise specified, the variables are as defined in formula I.
It is another object of the present invention to provide a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, and a pharmaceutically acceptable carrier or excipient thereof.
The pharmaceutical compositions of the present invention may be administered in a variety of known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical composition of the invention can be administered alone or in combination with other antitumor drugs. The oral composition may be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, suspensions, dispersions, and solutions. Common pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.
Sterile injectable compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.
The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for the particular patient, composition and mode of administration, and that is non-toxic to the patient. The dosage level selected will depend on a variety of factors including the activity of the particular compound of the invention or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the particular composition employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, general health and past medical history of the patient being treated, and like factors well known in the medical arts.
It is another object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer thereof in the manufacture of a medicament for the prevention and/or treatment of tumors.
The tumor comprises EB virus positive diffuse large B cell lymphoma, hepatocellular carcinoma or glioma.
The beneficial effects are that:
the invention synthesizes a class of derivatives of caffeic acid phenethyl ester, namely (E) -3- (5, 6-dihydroxyl-2-naphthylene) acrylate compounds. Pharmacological experiments prove that the caffeic acid phenethyl ester derivative has good anti-tumor effect, can effectively inhibit proliferation of tumor cells, and has good prospect in development of anti-tumor medicaments.
Detailed Description
The process for the preparation of the compounds of the general formula I according to the invention is described below in connection with specific examples, which, however, do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
The starting materials, reagents, etc. used in the examples of the present invention are all commercially available. The present invention can be prepared in salt form using salt forming methods commonly used in the art, for example: at room temperature, dissolving the compound into ethanol hydrochloride to react to generate hydrochloride; or adding benzenesulfonic acid into the mixture to react to obtain benzenesulfonate. Example 32 illustrates a method of synthesis of the hydrochloride salt of compound I-27, to which reference may be made for the synthesis of other salts, and other salts may be formed using methods commonly used in the art.
EXAMPLE 1 Synthesis of phenethyl (E) -3- (5, 6-dihydroxy-2-naphthylene) acrylate
6-bromo-2-naphthol (300 mg,1.34 mmol), 1, 3-bis (diphenylphosphine) propane (DPPP, 54mg,0.13 mmol), palladium acetate (Pd (OAc) 2,30mg,0.13 mmol) were placed in a schlenk tube, uniformly dispersed in 3ml DMF (N, N-dimethylformamide), triethylamine (541 mg,5.36 mmol), ethyl acrylate (1.3 g,13.40 mmol) were sequentially added, the reaction was heated under argon atmosphere at 115℃overnight, the completion of the reaction was monitored the next day, the system was cooled to room temperature, extracted with ethyl acetate and water, the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, the resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is chromatographed on a silica gel column with n-hexane: eluting with ethyl acetate (volume ratio of 8:1) mixed solvent to obtain white solid.
The above solid (300 mg,1.24 mmol) was dissolved in 4ml of ethanol, potassium hydroxide (208 mg,3.72 mmol) was added and stirred well for 3 hours, after the completion of the reaction was monitored, 20ml of water was added for dilution, the aqueous layer was washed 3 times with methylene chloride, the pH of the aqueous layer was adjusted to acidity with 1N hydrochloric acid, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, and the obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting white solid.
The above white solid (500 mg,2.33 mmol) was dissolved in 2ml of Tetrahydrofuran (THF) for use, phenethyl alcohol (2.33 mmol) and triphenylphosphine (TPP, 612mg,2.33 mmol) were further dissolved in 4ml of Tetrahydrofuran (THF), diisopropyl azodicarboxylate (DIAD, 463mg,2.33 mmol) was added dropwise to a solution of 4ml of phenethyl alcohol and triphenylphosphine in tetrahydrofuran under ice bath conditions, stirring was carried out thoroughly for 15min, the initially prepared solution of tetrahydrofuran was added dropwise to the reaction system in ice bath, and the system was moved to room temperature with stirring thoroughly. After TLC monitored complete reaction of starting materials, water quench was added. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is chromatographed on a silica gel column with n-hexane: eluting with ethyl acetate (volume ratio of 8:1) mixed solvent to obtain white solid.
The white solid (0.87 mmol) obtained in the previous step was dissolved in 2ml DMSO, 2-iodoxybenzoic acid (IBX, 269mg,0.96 mmol) was added to the reaction system, the mixture was stirred well, the reaction system turned from colorless to yellow, finally to orange-red, and after TLC monitoring the completion of the reaction of the raw materials, water was added to quench the reaction. Extraction with ethyl acetate, combining the organic phases, washing the organic phases with saturated sodium chloride solution, drying the obtained organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an orange-red solid.
The orange-red solid was dissolved in 2ml of acetonitrile (MeCN) and sodium dithionite (Na 2 S 2 O 4 166mg,0.96 mmol) was dissolved in 2ml water, and the aqueous sodium dithionite solution was slowly added to the acetonitrile solution of the above orange-red solid, and the mixture was stirred well under the protection of argon, whereby the reaction system gradually changed from orange-red to pale yellow. After the completion of the reaction, the reaction mixture was subjected to TLC and then to rotary evaporation under reduced pressure to remove acetonitrile, followed by extraction with ethyl acetate 3 times, and the organic phases were combined, dried over anhydrous sodium sulfate, and after the ethyl acetate was removed by rotary drying, sand was produced. The resulting sand column was chromatographed using n-hexane: eluting with ethyl acetate (volume ratio of 8:1) mixed solvent to obtain white solid as a compound.
1H NMR(300MHz,Methanol-d4)δ(ppm)7.86-7.55(m,5H),7.36-7.06(m,7H),6.48(d,J＝15.9Hz,1H),4.39(t,J＝7.0Hz,2H),3.00(t,J＝7.0Hz,2H)；13C NMR(75MHz,Methanol-d4)δ167.55,145.46,138.00,136.25,130.10,130.01,128.91,128.64,128.17,128.07,126.71,126.19,123.47,118.70,115.78,108.81,64.89,34.79.；MS(ESI)m/z,335.12[M+H] + 。
Example 2 (E) -phenylpropyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate
Reference is made to the synthesis of example 1.
1H NMR(300MHz,Methanol-d4)δ(ppm)7.86-7.55(m,5H),7.36-7.06(m,7H),6.48(d,J＝15.9Hz,1H),4.39(t,J＝7.0Hz,2H),3.00(t,J＝7.0Hz,2H),2.08(m,2H)；13CNMR(75MHz,Methanol-d4)δ167.55,145.46,138.00,136.25,130.10,130.01,128.91,128.64,128.17,128.07,126.71,126.19,123.47,118.70,115.78,108.81,64.89,34.79，21.06；MS(ESI)m/z,349.12[M+H] + 。
Example 3 (E) -3- (5, 6-dihydroxy-2-naphthylene) acrylic acid phenylbutyl ester
Reference is made to the synthesis of example 1.
1H NMR(300MHz,Methanol-d4)δ(ppm)7.86-7.55(m,5H),7.36-7.06(m,7H),6.48(d,J＝15.9Hz,1H),4.39(t,J＝7.0Hz,2H),3.00(t,J＝7.0Hz,2H),1.78(m,4H)；13CNMR(75MHz,Methanol-d4)δ167.55,145.46,138.00,136.25,130.10,130.01,128.91,128.64,128.17,128.07,126.71,126.19,123.47,118.70,115.78,108.81,64.89,34.79,21.06,20.56；MS(ESI)m/z,363.12[M+H] + 。
Example 4: biological Activity
The test method comprises the following steps: specific small molecule compounds were formulated as 100mM stock solutions.
For the suspended cells Farage and MC116, a density of 60. Mu.L per well was spotted into 96-well plates at 6000 cells/well, and the corresponding small molecule stock solution was prepared to 600. Mu.M, the drug-containing medium was diluted 3-fold, the working solution after the gradient dilution was added into the wells of the well-seeded cells at a volume of 30. Mu.L per well, and after culturing for 48 hours, the absorbance was measured by CCK8 method, and its IC was calculated using Graphpad Prism 50 Values.
For adherent cells Hep3B and U87, 3000 cells/well, per well100 mu L of density is spotted into a 96-well plate, a corresponding small molecule stock solution is prepared into 200 mu M and 3 times of gradient dilution drug-containing culture medium, the original culture medium is discarded after the cells are attached, the working solution after gradient dilution is added into the well of the culture plate of the seeded cells at the volume of 100 mu L per well, after culturing for 48 hours, the absorbance is measured by a CCK8 method, and the IC is calculated by using Graphpad Prism 50 Values. The experimental results are shown in Table 1. CAPE was used as a positive control.
Table 1 example IC of antiproliferative activity on 4 human cancer cell lines 50 Value (mu M)
Compounds of formula (I) Farage MC116 Hep3B U87
Example 1 0.873 2.546 48.338 61.584
Example 2 0.998 2.235 49.524 58.452
Example 3 0.924 1.687 50.127 53.696
CAPE 1.525 2.762 58.667 69.935
The Farage cells were originally derived from an EBV positive B cell lymphoma patient, and thus, the Farage cells were EBV positive; MC116 is a B lymphocyte, and is used for experimental study of B lymphocyte related diseases, including DLBCL study; the Hep3B cell is a liver cancer cell line and is widely used for researching liver cancer; u87 cell is a human glioblastoma cell line and is widely applied to glioma and cancer research.
As can be seen from Table 1, the compounds of example 1, example 2 and example 3 have IC's for various cell lines 50 The values are lower than CAPE, and can effectively inhibit the in vitro growth of EBV+DLBCL, EBV-DLBCL, hepatocellular carcinoma and glioblastoma cell lines.
The experimental results show that the compound provided by the invention can effectively inhibit the in vitro growth of EBV+DLBCL, EBV-DLBCL, HCC and glioblastoma cell lines.
The compound and the pharmaceutically acceptable salt thereof can effectively inhibit the in vitro growth of EBV+DLBCL, EBV-DLBCL, HCC and glioblastoma cell lines, and can be used as an effective ingredient in medicines. Therefore, the medicine containing the compound as an active ingredient can be used for preparing medicines for preventing and/or treating tumors.
As described above, although the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limiting the invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (9)

1. A (E) -3- (5, 6-dihydroxy-2-naphthylene) acrylate compound of formula I:
wherein,
r is selected from the group consisting of-H, -F, -Cl, -Br, -I, -CF 3 ，-CCl 3 ，-NO 2 ，-COCH 3 ，-OCOCH 3 ，-CH 3 ，-OCH 3 ，-OC 2 H 5 ，-NH 2 ，-NHSO 2 CH 3 ，-SO 2 NH 2 Or NHCOCH 3 ；
n=1, 2,3, 4 or 5.
2. A compound according to claim 1, characterized in that: the pharmaceutically acceptable salts include acid addition salts of compounds of formula I with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; also included are the acid salts of the compounds of formula I with inorganic bases.
3. A compound according to claim 2, characterized in that: the pharmaceutically acceptable salts include basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.
4. A compound according to claim 1, characterized in that it is selected from: (E) Phenyl ethyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl propyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl butyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl pentyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, phenyl hexyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylethyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylpropyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylbutyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylpentyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate, 2-fluorophenylhexyl 3- (5, 6-dihydroxy-2-naphthylene) acrylate.
5. The compound according to claim 4, characterized in that it is selected from:
6. a process for the preparation of a compound of formula I according to claim 1, characterized in that: the method comprises the following steps:
(1) Uniformly dispersing 6-bromo-2-naphthol, 1, 3-bis (diphenylphosphine) propane and palladium acetate in DMF, sequentially adding triethylamine and ethyl acrylate, heating and reacting at 115 ℃ under the protection of argon for overnight, and performing post-treatment to obtain a crude product, and performing silica gel column chromatography on the crude product to obtain a white solid;
(2) Dissolving the solid in ethanol, adding potassium hydroxide, stirring thoroughly, and reacting completely to obtain white solid;
(3) Dissolving the white solid in tetrahydrofuran for standby, dissolving an alcohol fragment and triphenylphosphine in tetrahydrofuran, adding diisopropyl azodicarboxylate into tetrahydrofuran solution of phenethyl alcohol and triphenylphosphine under ice bath condition, fully stirring, adding the initially prepared tetrahydrofuran solution into a reaction system in ice bath, moving the system to room temperature, fully stirring, post-treating to obtain a crude product, and carrying out silica gel column chromatography on the crude product to obtain the white solid;
(4) Dissolving the white solid in DMSO in the last step, adding 2-iodoxybenzoic acid into a reaction system, fully stirring, changing the reaction system from colorless to yellow, finally changing the reaction system into orange-red, and carrying out post treatment to obtain an orange-red solid;
(5) And (3) dissolving the orange-red solid in acetonitrile, adding an aqueous solution of sodium dithionite into the acetonitrile solution, fully stirring under the protection of argon, changing the reaction system from orange-red to pale yellow, performing post-treatment to obtain a crude product, and separating the crude product by column chromatography to obtain a white solid which is the target compound.
7. A pharmaceutical composition characterized by: a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutically acceptable carrier or excipient thereof.
8. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the prevention and/or treatment of tumors.
9. Use according to claim 8, characterized in that: the tumor comprises EB virus positive diffuse large B cell lymphoma, hepatocellular carcinoma or glioma.
CN202311157744.XA 2023-09-08 2023-09-08 Caffeic acid phenethyl ester derivative and preparation method and application thereof Pending CN117229146A (en)

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