CN114920639A - Novel method for synthesizing curcumin analogue - Google Patents
Novel method for synthesizing curcumin analogue Download PDFInfo
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- CN114920639A CN114920639A CN202210744538.8A CN202210744538A CN114920639A CN 114920639 A CN114920639 A CN 114920639A CN 202210744538 A CN202210744538 A CN 202210744538A CN 114920639 A CN114920639 A CN 114920639A
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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 47
- 238000000034 method Methods 0.000 title claims abstract description 37
- 230000002194 synthesizing effect Effects 0.000 title claims description 8
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 claims abstract description 65
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 39
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000002904 solvent Substances 0.000 claims abstract description 13
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007069 methylation reaction Methods 0.000 claims abstract description 8
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 5
- PMOWTIHVNWZYFI-AATRIKPKSA-N trans-2-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=CC=C1O PMOWTIHVNWZYFI-AATRIKPKSA-N 0.000 claims abstract description 5
- 230000011987 methylation Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 17
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 230000003113 alkalizing effect Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 25
- 238000000746 purification Methods 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 10
- 238000010898 silica gel chromatography Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 239000003513 alkali Substances 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 3
- 238000005949 ozonolysis reaction Methods 0.000 abstract description 3
- 239000002910 solid waste Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 229910000510 noble metal Inorganic materials 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- RCZMPCUUTSDNAJ-PHEQNACWSA-N (1e,4e)-1,5-bis(2-methoxyphenyl)penta-1,4-dien-3-one Chemical compound COC1=CC=CC=C1\C=C\C(=O)\C=C\C1=CC=CC=C1OC RCZMPCUUTSDNAJ-PHEQNACWSA-N 0.000 description 7
- 235000012754 curcumin Nutrition 0.000 description 7
- 229940109262 curcumin Drugs 0.000 description 7
- 239000004148 curcumin Substances 0.000 description 7
- 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 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical compound COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- FCMNDLLGEGVMQQ-BQYQJAHWSA-N methyl (e)-3-(2-methoxyphenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=CC=C1OC FCMNDLLGEGVMQQ-BQYQJAHWSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- -1 curcumin calcium salt Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical class O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- FNODWEPAWIJGPM-UHFFFAOYSA-N ethyl 2-methoxybenzoate Chemical compound CCOC(=O)C1=CC=CC=C1OC FNODWEPAWIJGPM-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000010970 precious metal Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 241000209524 Araceae Species 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 241000234299 Zingiberaceae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 229910052810 boron oxide Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- QAZYYQMPRQKMAC-FDGPNNRMSA-L calcium;(z)-4-oxopent-2-en-2-olate Chemical compound [Ca+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O QAZYYQMPRQKMAC-FDGPNNRMSA-L 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- JKWMSGQKBLHBQQ-UHFFFAOYSA-N diboron trioxide Chemical compound O=BOB=O JKWMSGQKBLHBQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/40—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with ozone; by ozonolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of a curcumin analogue, which has the following structural formula:
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis method of curcumin analogues.
Background
Curcumin and its analogues are compounds extracted from rhizomes of plants of Zingiberaceae and Araceae, and have various pharmaceutical effects. But is separated from natural products, and mass products cannot be rapidly obtained. There is a need to develop methods for industrial synthesis.
CN201611205572.9 discloses a method for artificially synthesizing curcumin and derivatives thereof. The method takes calcium acetylacetonate as an acetylacetone source, and obtains an intermediate (I) curcumin calcium salt through claisen-Schmitt ester condensation reaction with a corresponding benzaldehyde derivative and dehydration under the catalysis of a dehydrating agent tri-n-butyl borate; and hydrolyzing the intermediate (I) by a one-pot method to obtain a crude product, and purifying the crude product to obtain a final product curcumin and derivatives thereof. CN201911371013.9 provides a method for artificially synthesizing curcumin and its derivatives, which comprises reacting acetylacetone with boron oxide under weak acid conditions to generate a complex, protecting methylene between two ketone carbonyls, adding a catalyst, reacting the complex with vanillin (benzaldehyde derivative) to obtain curcumin derivative intermediate (I), and hydrolyzing to obtain curcumin derivative. However, there are many kinds of curcumin and derivatives thereof, and the compounds synthesized in the above two applications are structurally different from the analog to be synthesized in the present invention.
US20060276536 provides a method for artificially synthesizing curcumin and derivatives thereof, and covers curcumin analogs to be synthesized by the present invention. It uses 2-methoxy benzaldehyde and acetone to react, uses sodium hydroxide as alkali, and obtains the target product. The patent takes an ether/hexane mixed solution as a recrystallization solvent, wherein ether is a tube product, is flammable and explosive and is not suitable for being used as a solvent for mass production, and the product recrystallized by the mixed solvent has low purity and a crystal form structure is amorphous, so that the purity requirement cannot be met.
W02011029359 reports a synthesis method of the curcumin analogue. The method comprises the steps of reacting 2-methoxybenzaldehyde with acetone, dissolving metal sodium in methanol as alkali, and reacting to obtain a target product. The metal sodium is a dangerous metal product, is easy to explode and be inflammable when meeting water, and is not suitable for mass production. Meanwhile, the purification method is simple water washing, ethanol washing and acetone washing, and the purity of the obtained product is far from the requirement.
W02018086197 also reports the synthesis of this compound by reacting 2-methoxybenzaldehyde with acetone to give the desired product using K0 as base. The patent only washes with a large amount of water and a small amount of ethanol/water solution, and only obtains crude products of the curcumin analogue. The product prepared by the method has the same lower purity.
Disclosure of Invention
The invention aims to provide a novel synthesis method of curcumin analogues.
The technical scheme adopted by the invention is as follows: a novel method for synthesizing curcumin analog is provided.
a) The structural formula of the curcumin analogue is as follows:
b) the synthesis method comprises the following steps:
firstly, o-hydroxy trans-cinnamic acid reacts with ozone to obtain salicylaldehyde;
secondly, methyl iodide is used as a methylation reagent, and a product 2-methoxybenzaldehyde is obtained through methylation reaction;
and thirdly, reacting 2-methoxybenzaldehyde with acetone, adding an alkalizing agent, and recrystallizing to obtain the curcumin analogue.
Preferably, in the first reaction step, acetonitrile/water is used as a solvent in a volume ratio of 1-2: 1-2, methanol is used as a solvent for recrystallization, and the temperature is controlled between-15 ℃ and 0 ℃.
Preferably, in the step 1), after the reaction is completed, the reaction solution is fully blown by oxygen, then ethyl acetate is added for dilution, a separating funnel is used for layering, and an organic phase is collected; the aqueous phase was extracted with ethyl acetate until no product remained in the aqueous phase; mixing organic phases, washing with a saturated sodium bicarbonate solution and a saturated saline solution in sequence; the organic phase was collected and dried over anhydrous sodium sulfate.
Preferably, in the step 1), the product dried by anhydrous sodium sulfate is subjected to reduced pressure distillation to obtain colorless transparent liquid salicylaldehyde.
Preferably, in the second step of reaction, the molar ratio of the salicylaldehyde to the methyl iodide to the anhydrous potassium carbonate is 1: 1-1: 4, and the reaction temperature is 25-50 ℃; preferably, the molar ratio of the salicylaldehyde to the methyl iodide to the anhydrous potassium carbonate is 1: 3, and the temperature is 40 ℃.
Preferably, in the second reaction step, the solvent is selected from acetonitrile.
Preferably, the product 2-methoxybenzaldehyde obtained after the second reaction is extracted and dried with anhydrous sodium sulfate, and is directly put into the next reaction without further purification.
Preferably, in the third step of the reaction, the 2-methoxybenzaldehyde and acetone are added in a molar ratio of 2: 1.
Preferably, in the third reaction step, potassium methoxide is preferably selected as the alkalizing agent.
Preferably, the synthesis method is as follows: the final curcumin analogue is synthesized by adopting a three-step synthesis route, wherein the first step is ozonolysis, and salicylaldehyde is obtained by using a mixed solvent of acetonitrile and water (1: 1) and ozone for about 2-3 hours at the temperature of 0 ℃. The second step is methylation reaction, methyl iodide is used as a methylation reagent, potassium carbonate is used as alkali, and the reaction is carried out in acetonitrile overnight to obtain the product 2-methoxybenzaldehyde in the second step. The third step is that methyl salicylaldehyde reacts with acetone, potassium methoxide is used as alkali, and the curcumin analogue (1E, 4E) -1, 5-bis (2-methoxyphenyl) penta-1, 4-diene-3-ketone can be obtained after recrystallization.
The reaction formula is as follows:
another object of the present invention is to provide a process for preparing a high purity curcumin analog, said curcumin analog having the following structural formula:
the high-purity curcumin analogue is obtained by reacting 2-methoxybenzaldehyde with acetone, adding an alkalizing agent, taking methanol as a recrystallization solvent, and recrystallizing, wherein the purity is higher than 95%, preferably higher than 98%, and further preferably higher than 99%.
The invention has the following beneficial effects:
1. the invention adopts ozonolysis method in the first step of salicylaldehyde generation reaction, can effectively avoid using precious metal oxidant, and has little pollution to the environment. And the reaction product is purified by a reduced pressure distillation method, so that the purification by silica gel column chromatography is avoided, and the generation of solid waste and waste liquid can be effectively reduced. In the process of synthesizing 2-methoxybenzaldehyde in the second step, ethyl acetate and saturated sodium chloride solution are used for extraction for multiple times, an upper organic layer is taken, the solvent is evaporated under reduced pressure, further purification is not required by a silica gel chromatographic column, and the mixture can be directly put into the next step for reaction. In the third step of the reaction for generating the final product curcumin analogue, methanol can be adopted for recrystallization, and silica gel chromatographic columns are avoided for further purification. Compared with the prior art, the method does not use any precious metal catalyst or halogenated solvent, and does not generate a large amount of solid waste. Therefore, the method has the advantages of simple steps, easy operation, less pollution, high yield, convenient raw material obtaining and the like, and has wide application value.
2. The invention adopts methanol as a solvent for recrystallization to obtain crystalline crystals with the purity of more than 99 percent.
3. The invention provides a new synthetic route of curcumin analogues, adopts three-step synthesis, and is beneficial to new drug declaration.
In conclusion, the invention provides a new way to synthesize the curcumin analogue, and the method has the advantages of simple operation, easily obtained raw materials and easy industrial production. The method can obtain curcumin analogue with high yield and high purity by recrystallization without silica gel column chromatography.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive exercise.
FIG. 1 shows the chemical formula and mass spectra data for the product prepared in step B of example 1;
FIG. 2 shows the chemical formula and mass spectra data for the product prepared in step C of example 1;
FIG. 3 shows the chemical structure and nuclear magnetic data of the product prepared in step C of example 1;
FIG. 4 shows a reaction scheme of the present invention.
FIG. 5 shows the chemical structure and mass spectra data for the product prepared in comparative example 1-step A;
FIG. 6 shows the chemical structure and mass spectra data of the product prepared in comparative example 2-step A
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
Example 1
Step A: preparation of salicylaldehyde from ortho-hydroxy trans-cinnamic acid
Under the condition of ice salt bath (-10-0 ℃), o-hydroxy trans-cinnamic acid (20.0 g, 121.9 mmol) is added into a 250 ml round-bottom flask, dissolved in water (70 ml) and acetonitrile (70 ml), ozone gas is introduced into the suspension through a pipeline by using an ozone generator after the temperature is reduced to about-10 ℃, and the ozone is blown for about 2 hours under stirring until the suspension becomes a clear solution.
After the reaction was completed, the reaction solution was blown with oxygen for 2 minutes, diluted with ethyl acetate (200 ml), and separated into layers with a separatory funnel, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (100 ml × 2) until no product remained in the aqueous phase. The organic phases were combined, washed with saturated aqueous sodium bicarbonate (150 ml. times.2) and saturated brine (150 ml. times.1). The organic phase was collected, dried over anhydrous sodium sulfate and finally concentrated under reduced pressure. The resulting residue was purified by distillation under reduced pressure (vacuum pressure-680 mmHg), oil bath at 133 ℃ and collection of 108-110 ℃ fractions gave 9.3 g of colorless transparent liquid salicylaldehyde (yield: 62.8%).
And B: preparation of 2-methoxybenzaldehyde from salicylaldehyde
Salicylaldehyde (9.3 g, 76.2 mmol), methyl iodide (32.4 g, 228.7 mmol) and anhydrous potassium carbonate (31.5 g, 228.7 mmol) were dissolved in acetonitrile (90 ml) at room temperature, followed by heating to 40 ℃ and stirring the reaction under sealed conditions overnight. After completion of the reaction, the reaction was quenched by addition of water (50 ml), extracted with ethyl acetate (150 ml × 3), and the organic phases were combined, followed by washing with 1 mol/l aqueous hydrochloric acid (100 ml × 2), saturated brine (100 ml × 2), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure. 9.3 g of 2-methoxybenzaldehyde was obtained as an oil, which was directly used in the next step without further purification (yield: 89.7%). LCMS: RT ═ 1.70min, [ M + H] + =137.11,calcd for C 8 H 8 O 2 :136.15。
And C: preparation of (1E, 4E) -1, 5-bis (2-methoxyphenyl) pentan-1, 4-dien-3-one from 2-methoxybenzaldehyde
2-methoxybenzaldehyde (9.3 g, 68.3 mmol) was dissolved in methanol (90 ml) at room temperature, followed by addition of acetone (2.0 g, 34.1 mmol) and cooling to 0 ℃ with stirring. Solid potassium methoxide (4.8 g, 68.3 mmol) was weighed out and added to the reaction solution in portions. After the addition was complete, the reaction was warmed to room temperature and stirred continuously until a large amount of yellow solid precipitated. After the reaction was complete, the reaction was filtered and a yellow solid was collected and washed twice with methanol (50 ml). The yellow solid was then dissolved in dichloromethane (300 ml), washed with water (80 ml × 2), washed with saturated brine (80 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was recrystallized from methanol to give 5.7 g of (1E, 4E) -1, 5-bis (2-methoxyphenyl) penta-1, 4-dien-3-one as yellow crystals (yield 57.3%). LCMS: RT ═ 4.28min, [ M + H] + =295.14,calcd for C 19 H 18 O 3 :294.35。 1 H NMR(400MHz,CDCl 3 )δ8.12(d,J=16.1Hz,2H),7.68(dd,J=7.7,1.7Hz,2H),7.42(ddd,J=8.6,7.4,1.7Hz,2H),7.23(d,J=16.1Hz,2H),7.04(td,J=7.5,1.1Hz,2H),6.99(dd,J=8.4,1.0Hz,2H),3.97(s,6H)。
The purity of the product is more than 99 percent.
The reaction scheme of this example is as follows:
example 2
Steps A and C example 1 is the same except that step B is:
salicylaldehyde (9.3 g, 76.2 mmol), methyl iodide (32.4 g, 228.7 mmol) and anhydrous potassium carbonate (31.5 g, 228.7 mmol) were dissolved in acetonitrile (90 ml) at room temperature, then heated to 30 ℃ and the reaction was stirred under closed conditions overnight. After completion of the reaction, the reaction was quenched by addition of water (50 ml), extracted with ethyl acetate (150 ml × 3), and the organic phases were combined, followed by washing with 1 mol/l aqueous hydrochloric acid (100 ml × 2), saturated brine (100 ml × 2), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure. 8.27 g of 2-methoxybenzaldehyde was obtained as an oil, which was directly charged into the next step without further purification (yield: about 80%).
Example 3
Steps A and C example 1 is the same except that step B is:
salicylaldehyde (9.3 g, 76.2 mmol), methyl iodide (32.4 g, 228.7 mmol) and anhydrous potassium carbonate (31.5 g, 228.7 mmol) were dissolved in acetonitrile (90 ml) at room temperature, then heated to 25 ℃ and the reaction was stirred under closed conditions overnight. After completion of the reaction, the reaction was quenched by addition of water (50 ml), extracted with ethyl acetate (150 ml × 3), and the organic phases were combined, followed by washing with 1 mol/l aqueous hydrochloric acid (100 ml × 2), saturated brine (100 ml × 2), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure. 7.23 g of 2-methoxybenzaldehyde was obtained as an oil, which was directly used in the next step without further purification (yield: about 70%).
Example 4
Steps A and C example 1 is the same except that step B is:
salicylaldehyde (9.3 g, 76.2 mmol), methyl iodide (21.6 g, 152.5 mmol) and anhydrous potassium carbonate (21.0 g, 152.47 mmol) were dissolved in acetonitrile (90 ml) at room temperature, followed by heating to 40 ℃ and stirring the reaction under closed conditions overnight. After the reaction was completed, the reaction was quenched by adding water (50 ml), extracted with ethyl acetate (150 ml × 3), and the organic phases were combined, followed by washing with 1 mol/l aqueous hydrochloric acid (100 ml × 2), saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 6.21 g of 2-methoxybenzaldehyde was obtained as an oil, which was directly charged into the next step without further purification (yield: about 60%).
Example 5
Steps A and C example 1 is the same except that step B is:
salicylaldehyde (9.3 g, 76.2 mmol), methyl iodide (10.8 g, 76.2 mmol) and anhydrous potassium carbonate (31.5 g, 228.7 mmol) were dissolved in acetonitrile (90 ml) at room temperature, followed by heating to 40 ℃ and stirring the reaction under closed conditions overnight. After completion of the reaction, the reaction was quenched by addition of water (50 ml), extracted with ethyl acetate (150 ml × 3), and the organic phases were combined, followed by washing with 1 mol/l aqueous hydrochloric acid (100 ml × 2), saturated brine (100 ml × 2), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure. 5.15 g of 2-methoxybenzaldehyde was obtained as an oil, which was directly used in the next step without further purification (yield: about 50%).
The results of step 2 of examples 1 to 5 are as follows:
from the comparison, when the feeding ratio A: B: C is 1: 3, the reaction temperature is controlled at 40 ℃ and above, and the yield of the reaction is the highest and reaches 90%. At 40 deg.C, when the ratio of A to B to C is 1 to 3, the yield is up to 90%.
Comparative example 1
Step A: preparation of 2-methoxybenzoic thioesters from 2-methoxybenzoic acid
2-Methoxybenzoic acid (10.0 g, 65.7 mmol) and ethanethiol (4.3 g, 69.0 mmol) were dissolved in a dry solution of dichloromethane (100 ml) at room temperature, followed by the addition of 4-dimethylaminopyridine (4.0 g, 32.8 mmol) and dicyclohexylcarbodiimide (27.1 g, 131.4 mmol) in that order. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was filtered through celite and washed with dichloromethane (200 ml). The resulting organic layer was washed with 1 mol/l aqueous hydrochloric acid (100 ml. times.3) and saturated brine (100 ml. times.1). Collecting the organic phase, using anhydrous sulfuric acidSodium drying, and concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 15: 1) to obtain 10.3 g of 2-methoxybenzoic acid ethyl thioester as a white solid (yield: 79.9%). LCMS: RT 2.02min, [ M-EtS] + =135.20,calcd for C 8 H 7 O 2 :135.14。
And B: preparation of 2-methoxybenzaldehyde from 2-methoxybenzoic acid ethyl thioester
Ethyl 2-methoxybenzoate (10.3 g, 52.6 mmol) was dissolved in a dry dichloromethane (100 ml) solution at room temperature, and triethylsilane (18.3 g, 157.7 mmol) and 10% Pd/C (660.2 mg) were added sequentially. While nitrogen was replaced three times, stirring was continued overnight under nitrogen atmosphere. After the reaction was complete, it was filtered through celite and washed with dichloromethane (200 ml). The obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 15: 1) to obtain 1.3 g of 2-methoxybenzaldehyde as a white solid (yield: 18.2%). LCMS: RT ═ 1.70min, [ M + H] + =137.11,calcd for C 8 H 8 O 2 :136.15。
And C: preparation of (1E, 4E) -1, 5-bis (2-methoxyphenyl) pentan-1, 4-dien-3-one from 2-methoxybenzaldehyde
At room temperature, 2-methoxybenzaldehyde (1.3 g, 9.5 mmol) was dissolved in methanol (15 ml), followed by the addition of acetone (275.5 mg, 4.7 mmol) and cooling to 0 ℃ with stirring. Solid potassium methoxide (1.3 g, 19.0 mmol) was weighed out and added to the reaction solution in portions. After the addition was complete, the reaction was warmed to room temperature and stirred continuously until a large amount of yellow solid precipitated. After the reaction is completed, the reaction solution is filtered, a yellow solid is collected, and methanol is usedWashed twice (50 ml). The yellow solid was then dissolved in dichloromethane (300 ml), washed with water (80 ml × 2), washed with saturated brine (80 × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was recrystallized from methanol to give 786.8 mg of (1E, 4E) -1, 5-bis (2-methoxyphenyl) pentan-1, 4-dien-3-one as yellow crystals (yield 56.2%). LCMS: RT 4.28min, [ M + H ═] + =295.14,calcd for C 19 H 18 O 3 :294.35。 1 H NMR(400MHz,CDCl 3 )δ8.12(d,J=16.1Hz,2H),7.68(dd,J=7.7,1.7Hz,2H),7.42(ddd,J=8.6,7.4,1.7Hz,2H),7.23(d,J=16.1Hz,2H),7.04(td,J=7.5,1.1Hz,2H),6.99(dd,J=8.4,1.0Hz,2H),3.97(s,6H)。
Comparative example 2:
step A: preparation of (E) -3- (2-methoxyphenyl) acrylic acid methyl ester from o-hydroxy trans-cinnamic acid
Ortho-hydroxy trans-cinnamic acid (10.0 g, 61.0 mmol), methyl iodide (34.6 g, 244.0 mmol) and anhydrous potassium carbonate (33.9 g, 244.0 mmol) were dissolved in acetonitrile (100 ml) at room temperature, followed by heating to 40 ℃ and stirring under closed conditions overnight. After completion of the reaction, the reaction was quenched by addition of water (50 ml), extracted with ethyl acetate (150 ml × 3), and the organic phases were combined, followed by washing with 1 mol/l aqueous hydrochloric acid (100 ml × 2), saturated brine (100 ml × 2), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure. 9.3 g of methyl (E) -3- (2-methoxyphenyl) acrylate as an oil were obtained and charged directly into the next step without further purification (yield: 79.5%). LCMS: RT 2.79min, [ M-OCH 3 ] + =161.00,calcd for C 10 H 9 O 2 :161.18。
And B, step B: preparation of 2-methoxybenzaldehyde from (E) -3- (2-methoxyphenyl) acrylic acid methyl ester
Methyl (E) -3- (2-methoxyphenyl) acrylate (9.3 g, 48.4 mmol) was added to a 250 ml round bottom flask in an ice salt bath and dissolved in acetonitrile (100 ml) solution, after the temperature was reduced to about-10 ℃, ozone gas was bubbled into the suspension through the tube using an ozone generator and the ozone was bubbled for about 2 hours with stirring until the suspension became clear. After the reaction was completed, the reaction solution was blown with oxygen for 2 minutes, diluted with ethyl acetate (200 ml), and separated into layers with a separatory funnel, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (100 ml × 2) until no product remained in the aqueous phase. The organic phases were combined, washed with saturated aqueous sodium bicarbonate (150 ml. times.2) and saturated brine (150 ml. times.1). The organic phase was collected, dried over anhydrous sodium sulfate and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 15: 1) to give 4.1 g of 2-methoxybenzaldehyde as a white solid. (yield: 62.8%). LCMS: RT ═ 1.70min, [ M + H] + =137.11,calcd for C 8 H 8 O 2 :136.15。
And C: preparation of (1E, 4E) -1, 5-bis (2-methoxyphenyl) pentan-1, 4-dien-3-one from 2-methoxybenzaldehyde
At room temperature, 2-methoxybenzaldehyde (4.1 g, 30.1 mmol) was dissolved in methanol (15 ml), followed by the addition of acetone (874.2 mg, 15.0 mmol) and cooling to 0 ℃ with stirring. Solid potassium methoxide (2.1 g, 30.1 mmol) was weighed out and added to the reaction solution in portions. After the addition was complete, the reaction was warmed to room temperature and stirred continuously until a large amount of yellow solid precipitated. After the reaction was complete, the reaction was filtered and a yellow solid was collected and washed twice with methanol (50 ml). The yellow solid was then dissolved in dichloromethane (300 ml), washed with water (80 ml × 2) and saturatedThe extract was washed with brine (80X 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was recrystallized from methanol to give 553.9 mg of (1E, 4E) -1, 5-bis (2-methoxyphenyl) pentan-1, 4-dien-3-one as yellow crystals (yield 12.5%). LCMS: RT 4.28min, [ M + H ═] + =295.14,calcd for C 19 H 18 O 3 :294.35。 1 H NMR(400MHz,CDCl 3 )δ8.12(d,J=16.1Hz,2H),7.68(dd,J=7.7,1.7Hz,2H),7.42(ddd,J=8.6,7.4,1.7Hz,2H),7.23(d,J=16.1Hz,2H),7.04(td,J=7.5,1.1Hz,2H),6.99(dd,J=8.4,1.0Hz,2H),3.97(s,6H)。
In conclusion, the yield of step B in comparative example 1 is as low as 18.2%, and both step A and step B need to be purified by silica gel column chromatography, which increases the cost and production period of the subsequent process. After the reaction of step B in comparative example 2 is completed, some pigment byproducts are extremely difficult to remove, and although the pigment byproducts are purified twice by silica gel column chromatography, the byproducts which cannot be detected by thin layer chromatography and LCMS greatly influence the reaction of the next step C, so that only a few products are separated out in step C. In all the embodiments, the step A can be purified cleanly only by reduced pressure distillation, the step B can be used for purifying the product only by simple extraction and washing, the step C can be recrystallized, the post-treatment is very simple to operate, and the method is high in overall yield and suitable for process production.
Claims (10)
2. The method for purifying a high-purity curcumin analog as claimed in claim 1, wherein said high purity is more than 99%.
3. The method for purifying a high-purity curcumin analog as claimed in claim 1, wherein said high purity is a purity of more than 98%.
4. The method for purifying a high-purity curcumin analog as claimed in claim 1, wherein said high purity is more than 95% purity.
5. The method for purifying a high-purity curcumin analog as described in any one of the above claims, wherein the method for synthesizing the curcumin analog comprises the steps of: step 3), reacting 2-methoxybenzaldehyde with acetone, and adding an alkalizing agent;
and/or step 2) using methyl iodide as a methylation reagent to carry out methylation reaction on the salicylaldehyde to obtain a product 2-methoxybenzaldehyde;
and/or 1) reacting o-hydroxy trans-cinnamic acid with ozone to obtain salicylaldehyde.
6. The method for purifying a high-purity curcumin analog as claimed in claim 5, wherein: in the step 1), after the reaction is completed, fully blowing the reaction liquid by using oxygen, adding ethyl acetate for dilution, layering by using a separating funnel, and collecting an organic phase; extracting the aqueous phase with ethyl acetate until no product remains in the aqueous phase; mixing organic phases, washing with a saturated sodium bicarbonate solution and a saturated saline solution in sequence; the organic phase was collected and dried over anhydrous sodium sulfate.
7. The method for purifying a high-purity curcumin analog as claimed in claim 6, wherein the product dried over anhydrous sodium sulfate in the step 1) is subjected to distillation under reduced pressure to obtain colorless transparent liquid salicylaldehyde.
8. The method for purifying a high-purity curcumin analog as claimed in claim 5, wherein in the step 2), the molar ratio of salicylaldehyde to methyl iodide to anhydrous potassium carbonate is 1: 1 to 1: 4, and the reaction temperature is 25 to 50 ℃;
and/or in the step 2), the solvent is acetonitrile;
and/or extracting the product 2-methoxybenzaldehyde after the reaction in the step 2), drying the product by using anhydrous sodium sulfate, and directly putting the dried product into the next reaction.
9. The method for purifying a high-purity curcumin analogue as claimed in claim 5, wherein in the step 3), the dosage ratio of the 2-methoxybenzaldehyde to the acetone is (1-3): 1.
10. the method for purifying a high-purity curcumin analog as claimed in claim 5, wherein in the step 3), potassium methoxide is used as an alkalizing agent.
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