CN114195762A - Curcumin analogue and synthesis method thereof - Google Patents
Curcumin analogue and synthesis method thereof Download PDFInfo
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- CN114195762A CN114195762A CN202111541416.0A CN202111541416A CN114195762A CN 114195762 A CN114195762 A CN 114195762A CN 202111541416 A CN202111541416 A CN 202111541416A CN 114195762 A CN114195762 A CN 114195762A
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical class C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 71
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 229940125898 compound 5 Drugs 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 13
- 229940126214 compound 3 Drugs 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 abstract description 21
- 235000012754 curcumin Nutrition 0.000 abstract description 20
- 229940109262 curcumin Drugs 0.000 abstract description 20
- 239000004148 curcumin Substances 0.000 abstract description 20
- 239000000126 substance Substances 0.000 abstract description 7
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 239000003963 antioxidant agent Substances 0.000 abstract description 2
- 230000003078 antioxidant effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000007760 free radical scavenging Effects 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002835 absorbance Methods 0.000 description 6
- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- -1 curcumin compound Chemical class 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 235000003392 Curcuma domestica Nutrition 0.000 description 2
- 244000008991 Curcuma longa Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- RSAHICAPUYTWHW-UHFFFAOYSA-N Hexahydrocurcumin Chemical compound C1=C(O)C(OC)=CC(CCC(O)CC(=O)CCC=2C=C(OC)C(O)=CC=2)=C1 RSAHICAPUYTWHW-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 235000003373 curcuma longa Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 235000013976 turmeric Nutrition 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- UEPVWRDHSPMIAZ-IZTHOABVSA-N (1e,4z,6e)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-IZTHOABVSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- HJTVQHVGMGKONQ-LUZURFALSA-N Curcumin II Natural products C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=CC(O)=CC=2)=C1 HJTVQHVGMGKONQ-LUZURFALSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000234299 Zingiberaceae Species 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 108010010165 curculin Proteins 0.000 description 1
- NMRUIRRIQNAQEB-UHFFFAOYSA-N demethoxycurcumin Natural products OC(=CC(C=CC1=CC(=C(C=C1)O)OC)=O)C=CC1=CC=C(C=C1)O NMRUIRRIQNAQEB-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- UEPVWRDHSPMIAZ-UHFFFAOYSA-N p-hydroxycinnamoyl feruloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(O)=CC(=O)C=CC=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Dermatology (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a curcumin analogue and a synthesis method thereof, and the structure of the curcumin analogue is shown as follows:
wherein R is-OH or-OCH3The curcumin analogue prepared by the invention has higher free radical scavenging activity and chemical stability superior to that of curcumin, can be used for preparing antioxidant and anti-inflammatory skin care products or medicines, and has the advantages of simple preparation method, easy operation, cheap and easily obtained raw materials, higher reaction efficiency and yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a curcumin analogue and a synthesis method thereof.
Background
Curcumin (curculin, 1, 7-bis (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione) is a natural polyphenol chemical pigment extracted from plants of Zingiberaceae, and has molecular formula of C21H20O6The molecular weight is 368.12, and the structure is shown below.
The curcumin compound is the main effective component of the turmeric, and the content of the curcumin compound in the pigment extracted from the turmeric is about 70 percent. In addition to curcumin, demethoxycurcumin, hexahydrocurcumin and the like are also available.
The previous researches on the physiological activity of curcumin by researchers show that curcumin and analogues thereof have excellent pharmaceutical activities of resisting oxidation, inflammation, tumor cell proliferation, rheumatism, bacteria, hepatotoxicity and the like. However, curcumin has poor chemical structure stability and is less absorbed in a human body, so that the bioavailability of curcumin is reduced, and the clinical application of curcumin is limited, therefore, in recent years, curcumin is taken as a lead compound, and structural modification is carried out on the basis of the structure of curcumin to synthesize a large amount of derivatives and analogues of curcumin.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the technical problems, the invention provides a curcumin analogue and a synthesis method thereof.
The adopted technical scheme is as follows:
a curcumin analogue has the following structure:
wherein R is-OH and/or-OCH3。
R is a substituent selected from-OH and-OCH3One or two of the above-mentioned two compounds are combined, and the number of R is greater than or equal to 1.
Further, R is 3-OH or 3-OCH3Or 4-OH or 4-OCH3Or 4-OH and 3-OCH3Or 3-OH and 4-OCH3Any one of them.
Further, R is 4-OH and/or 3-OCH3。
Wherein, 3-OH, 3-OCH3、4-OH、4-OCH3Respectively represents a hydroxyl group para to the vinyl group, a methoxy group para to the vinyl group, a hydroxyl group meta to the vinyl group, and a methoxy group meta to the vinyl group.
The invention also provides a synthesis method of the curcumin analogue, which comprises the following steps:
S1：
reacting the compound 1 with the compound 2 to obtain a compound 3;
S2：
reacting the compound 3 with the compound 4 to obtain a compound 5;
S3：
and reacting the compound 5 with the compound 6 to obtain the curcumin analogue.
Further, S1 is specifically as follows:
adding the compound 1 into a solvent, stirring to dissolve the compound, adding triethylamine and a compound 2, reacting for 3-5 hours, adding a saturated ammonium chloride solution into a reaction solution, quenching, extracting the reaction solution for 3-5 times by ethyl acetate, combining organic phases, washing the organic phase by a saturated sodium chloride solution and drying by anhydrous sodium sulfate to obtain a first crude product, and purifying the first crude product by column chromatography to obtain a compound 3.
Further, S2 is specifically as follows:
adding the compound 3 into a solvent, stirring to dissolve the compound, adding piperidine and the compound 4, heating to 50-55 ℃, reacting for 6-8h, recovering to room temperature, adding silica gel into a reaction solution, concentrating under reduced pressure, and purifying by column chromatography to obtain a compound 5.
Further, S3 is specifically as follows:
adding the compound 5 into a solvent, stirring to dissolve the compound, adding the compound 6 and a catalyst, heating to 80-85 ℃, reacting for 10-15h, decompressing and concentrating to remove the solvent, adjusting the pH of the system to 7-8 by using a sodium hydroxide solution, extracting for 3-5 times by using ethyl acetate, combining organic phases, washing the organic phases by using a saturated sodium chloride solution and drying the organic phases by using anhydrous sodium sulfate to obtain a second crude product, and purifying the second crude product to obtain the curcumin analogue.
Further, the molar ratio of the compound 1 to the compound 2 to the triethylamine is 1: 1.2: 1.5-2.25;
the molar ratio of the compound 3 to the compound 4 to the piperidine is 1: 1.25-1.75: 1 to 1.75;
the molar ratio of the compound 5 to the compound 6 is 1: 1-3.
Further, the solvent is any one of dichloromethane, dichloroethane, acetonitrile, acetic acid, DMF, DMSO, THF and 1, 4-dioxane.
Further, the catalyst is any one of concentrated hydrochloric acid, concentrated sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid, and the molar ratio of the catalyst to the compound 5 is 4-6: 1.
the invention has the beneficial effects that:
the curcumin analogue prepared by the invention has higher free radical scavenging activity and better chemical stability than curcumin, can be used for preparing antioxidant and anti-inflammatory skin care products or medicines, and has the advantages of simple preparation method, easy operation, cheap and easily obtained raw materials, and higher reaction efficiency and yield.
Detailed Description
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1:
a method for synthesizing curcumin analogues comprises the following steps:
S1：
adding 290mg (2mmol) of compound 1 (3-indolal) into a 25mL round-bottom flask with magnetons at room temperature, adding 5mL acetonitrile serving as a solvent to obtain a clear yellow solution, adding 4mmol triethylamine while stirring at room temperature, dropwise adding 2.4mmol of compound 2 (benzoyl chloride) into a reaction bottle after 30min, continuing to react for 3h, adding 5mL of saturated ammonium chloride solution to quench the reaction, extracting with 5mL of multiplied by 3 ethyl acetate, combining organic phases, washing with 15mL of saturated sodium chloride solution, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain a first crude product, carrying out column chromatography on silica gel to obtain a compound 3, wherein an eluent is petroleum ether, ethyl acetate is 4:1, the yield is 79.7%,1HNMR(400MHz，CDCl3)δ(ppm)10.08(s,1H),8.41-8.29(m，2H)，7.97(s，1H)，7.80(d，J＝7.2Hz，2H)，7.70(d，J＝7.4Hz，1H)，7.61(t，J＝7.6Hz,2H),7.49(dd,J＝10.0，3.7Hz，2H)，HRMS-ESI(m/z)：calcd for C16H11NO2[M+H]+：250.0863；found 250.0868。
S2：
accurately weighing compound 3(249mg, 1mmol) in a 50mL dry round bottom flask, placing appropriate magneton in the round bottom flask, adding 10mL THF as solvent to dissolve completely, adding 1.5mmol piperidine and 1.5mmol compound 4, reacting at 50 deg.C for 6hAdding 2g silica gel, decompressing, concentrating and evaporating THF, obtaining compound 5 after column chromatography, the eluent is methanol and ethyl acetate which is 1:8, the yield is 56.5%,1H NMR(400MHz，MeOD)δ(ppm)8.01(s，1H)，7.69(d，J＝7.7Hz，1H)，7.49(s，1H)，7.35(d，J＝7.9Hz，1H)，7.11(ddd，J＝14.9，14.1，7.0Hz，2H)，3.60(d，J＝1.4Hz，2H)，2.79(t，J＝6.2Hz，2H)，2.53(t，J＝6.2Hz，2H)，2.45(s，3H)，HRMS-ESI(m/z)：calcd for C15H16N2O[M+H]+：241.1335；found 241.1339。
S3：
accurately weighing compound 5(120mg, 0.5mmol) in a 30mL pressure-resistant reaction tube, adding 3mL acetic acid as a solvent to completely dissolve the compound, adding compound 6(152.5mg, 1.25mmol) and 2.5mmol trifluoroacetic acid respectively, reacting at 80 ℃ for 12 hours, distilling under reduced pressure to remove acetic acid, adjusting the system pH to 7 with 0.5M sodium hydroxide solution, extracting with 5mL multiplied by 3 ethyl acetate, combining organic phases, washing with 15mL saturated sodium chloride solution, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain a second crude product, purifying by column chromatography to obtain a target product, wherein the eluent is methanol, ethyl acetate is 1:8, the yield is 54.5%,1HNMR(400MHz,MeOD)δ(ppm)8.25(s，1H)，7.83(d，J＝7.6Hz，1H)，7.79(s，1H),，7.63(s，1H)，7.46(d，J＝7.7Hz，1H)，7.35(d，J＝8.5Hz，2H),7.28-7.17(m，2H)，6.88(d，J＝8.5Hz，2H)，3.86(d，J＝10.3Hz，4H)，2.59(s，3H)，HRMS-ESI(m/z)：calcd for C22H20N2O2[M+H]+:345.1598；found345.1601。
example 2:
a method for synthesizing curcumin analogues comprises the following steps:
accurately and accurately weighed chemical combinationAdding 3mL of acetic acid serving as a solvent into a 30mL pressure-resistant reaction tube to completely dissolve a substance 7(120mg, 0.5mmol), adding a compound 8(233.2mg, 1.25mmol) and 2.5mmol of trifluoroacetic acid respectively, reacting at 80 ℃ for 12 hours, distilling under reduced pressure to remove the acetic acid, adjusting the pH of the system to 7 by using 0.5M sodium hydroxide solution, extracting by using 5mL of multiplied by 3 ethyl acetate, combining organic phases, washing by using 15mL of saturated sodium chloride solution, drying by using anhydrous sodium sulfate, distilling under reduced pressure to obtain a second crude product, purifying by using column chromatography to obtain a target product, wherein an eluent is methanol, ethyl acetate is 1:8, and the yield is 52.8%;1H NMR(400MHz，MeoD)7.95(1H，s)，7.78(1H，d，J＝7.7Hz)，7.71(1H，d，J＝2.7Hz)，7.57(1H，s)，7.49(2H，d，J＝7.9Hz)，7.25-7.16(2H，m)，6.94(1H，dd，J＝8.5Hz，1.7Hz)，6.87(2H，d，J＝8.1＝Hz)，3.83(3H，s)，3.73(2H，s)，3.70(2H，s)，2.47(3H，s)；RMS-ESI(m/z)：calcd for C23H22N2O3[M+H]+:375.1703；found 375.1707。
and (3) performance testing:
the test is carried out at room temperature, curcumin analogs prepared in examples 1 and 2 and curcumin are respectively dissolved in DMSO to prepare sample solutions with different concentrations, then 20 mu L of the sample solutions with different concentrations are respectively added into 980 mu L of DPPH & absolute ethyl alcohol solution with the concentration of 8mg/L, the mixture is subjected to light-shielding reaction for 30min, the absorbance As at 517nm is measured by taking 20 mu L of the sample solution and 980 mu L of absolute ethyl alcohol As references, the absorbance Ac of 20 mu LDMSO and 980 mu LDPPH & is measured by taking the absolute ethyl alcohol As references, all measured values are three-time average values, and the DPPH & clearance rate of the sample is calculated according to the following formula.
DPPH.Clearance (%) - (1-As/Ac). times.100%
The concentration is then plotted against the clearance and the IC of each compound is determined from the clearance curve50The values (concentrations at which the curcumin analogs achieve 50% clearance of DPPH radicals) are given in table 1 below:
table 1:
| IC50value/(μmol/L) | |
| Example 1 | 8.92 |
| Example 2 | 12.64 |
| Curcumin (curcumin) | 31.60 |
DPPH is a relatively stable nitrogen-containing free radical, when the free radical is reduced to hydrazine after reacting with a hydrogen-donating group, DPPH measurement is widely used for evaluating the activity of a compound for removing free radicals and the hydrogen atom transfer capacity, and the tests show that compared with curcumin, the curcumin analogue prepared by the invention has improved free radical removal capacity, and the inventor has an effect on structural modification of curcumin.
② preparing curcumin analogue and curcumin solution prepared in the invention in the embodiment 1 and 2, adjusting the pH value of the solution to 12 and 2 with sodium hydroxide and acetic acid, testing the absorbance, placing the solution in 50 ℃ water bath, testing the absorbance after 12h, calculating the absorbance decrease rate, the result is shown in the following table 2:
table 2:
the absorbance decrease indicates that the compound is decomposed, and as can be seen from table 2 above, the curcumin analogue prepared by the invention has higher chemical stability at higher temperature and in acid-base environment than curcumin.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A curcumin analogue is characterized in that the structure is shown as follows:
wherein R is-OH and/or-OCH3。
2. A curcumin analog as claimed in claim 1 wherein R is 3-OH or 3-OCH3Or 4-OH or 4-OCH3Or 4-OH and 3-OCH3Or 3-OH and 4-OCH3Any one of them.
3. The method for synthesizing a curcumin analog of claim 2 wherein R is 4-OH and/or 3-OCH3。
4. A method of synthesis of a curcumin analogue as claimed in any one of claims 1 to 3 comprising the steps of:
S1：
reacting the compound 1 with the compound 2 to obtain a compound 3;
S2：
reacting the compound 3 with the compound 4 to obtain a compound 5;
S3：
and reacting the compound 5 with the compound 6 to obtain the curcumin analogue.
5. The method for synthesizing a curcumin analog as claimed in claim 4, wherein S1 is specifically as follows:
adding the compound 1 into a solvent, stirring to dissolve the compound, adding triethylamine and a compound 2, reacting for 3-5 hours, adding a saturated ammonium chloride solution into a reaction solution, quenching, extracting the reaction solution for 3-5 times by ethyl acetate, combining organic phases, washing the organic phase by a saturated sodium chloride solution and drying by anhydrous sodium sulfate to obtain a first crude product, and purifying the first crude product by column chromatography to obtain a compound 3.
6. The method for synthesizing a curcumin analog as claimed in claim 5, wherein S2 is specifically as follows:
adding the compound 3 into a solvent, stirring to dissolve the compound, adding piperidine and the compound 4, heating to 50-55 ℃, reacting for 6-8h, recovering to room temperature, adding silica gel into the reaction liquid, concentrating under reduced pressure, and purifying by column chromatography to obtain a compound 5.
7. The method for synthesizing a curcumin analog as claimed in claim 6, wherein S3 is specifically as follows:
adding the compound 5 into a solvent, stirring to dissolve the compound, adding the compound 6 and a catalyst, heating to 80-85 ℃, reacting for 10-15h, decompressing and concentrating to remove the solvent, adjusting the pH of the system to 7-8 by using a sodium hydroxide solution, extracting for 3-5 times by using ethyl acetate, combining organic phases, washing the organic phases by using a saturated sodium chloride solution and drying the organic phases by using anhydrous sodium sulfate to obtain a second crude product, and purifying the second crude product to obtain the curcumin analogue.
8. The method for synthesizing a curcumin analog as claimed in claim 7, wherein the molar ratio of the compound 1, the compound 2 and the triethylamine is 1: 1.2: 1.5-2.25;
the molar ratio of the compound 3 to the compound 4 to the piperidine is 1: 1.25-1.75: 1 to 1.75;
the molar ratio of the compound 5 to the compound 6 is 1: 1-3.
9. A process for the synthesis of a curcumin analog as claimed in any one of claims 5 to 7 wherein said solvent is any one of dichloromethane, dichloroethane, acetonitrile, acetic acid, DMF, DMSO, THF, 1, 4-dioxane.
10. The method for synthesizing a curcumin analog as claimed in claim 7, wherein said catalyst is any one of concentrated hydrochloric acid, concentrated sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid, and the molar ratio of said catalyst to compound 5 is 4-6: 1.
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