CN112457192A - Synthetic method of paradol - Google Patents
Synthetic method of paradol Download PDFInfo
- Publication number
- CN112457192A CN112457192A CN202011212907.6A CN202011212907A CN112457192A CN 112457192 A CN112457192 A CN 112457192A CN 202011212907 A CN202011212907 A CN 202011212907A CN 112457192 A CN112457192 A CN 112457192A
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- CN
- China
- Prior art keywords
- acid
- reaction
- methoxyphenyl
- potassium
- diethyl malonate
- Prior art date
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- CZNLTCTYLMYLHL-UHFFFAOYSA-N [6]-Paradol Chemical compound CCCCCCCC(=O)CCC1=CC=C(O)C(OC)=C1 CZNLTCTYLMYLHL-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 235000002780 gingerol Nutrition 0.000 claims abstract description 16
- NLDDIKRKFXEWBK-AWEZNQCLSA-N gingerol Chemical compound CCCCC[C@H](O)CC(=O)CCC1=CC=C(O)C(OC)=C1 NLDDIKRKFXEWBK-AWEZNQCLSA-N 0.000 claims abstract description 14
- JZLXEKNVCWMYHI-UHFFFAOYSA-N gingerol Natural products CCCCC(O)CC(=O)CCC1=CC=C(O)C(OC)=C1 JZLXEKNVCWMYHI-UHFFFAOYSA-N 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 4-acetoxyl-3-methoxyphenyl Chemical group 0.000 claims abstract description 7
- BRIMLUZGZWFOST-UHFFFAOYSA-N [4-(chloromethyl)-2-methoxyphenyl] acetate Chemical compound COC1=CC(CCl)=CC=C1OC(C)=O BRIMLUZGZWFOST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 6
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 5
- 238000001308 synthesis method Methods 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 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
- 239000002585 base Substances 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 5
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 5
- 235000012141 vanillin Nutrition 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005882 aldol condensation reaction Methods 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000000203 mixture 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
- 238000002360 preparation method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- OQWKEEOHDMUXEO-UHFFFAOYSA-N (6)-shogaol Natural products CCCCCC=CC(=O)CCC1=CC=C(O)C(OC)=C1 OQWKEEOHDMUXEO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- OQWKEEOHDMUXEO-BQYQJAHWSA-N [6]-Shogaol Chemical compound CCCCC\C=C\C(=O)CCC1=CC=C(O)C(OC)=C1 OQWKEEOHDMUXEO-BQYQJAHWSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- VKCYHJWLYTUGCC-UHFFFAOYSA-N nonan-2-one Chemical compound CCCCCCCC(C)=O VKCYHJWLYTUGCC-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OJYLAHXKWMRDGS-UHFFFAOYSA-N zingerone Chemical compound COC1=CC(CCC(C)=O)=CC=C1O OJYLAHXKWMRDGS-UHFFFAOYSA-N 0.000 description 2
- AXMBOMODZLJDKX-UHFFFAOYSA-N 1-(4-hydroxy-3-methoxyphenyl)dec-1-en-3-one Chemical compound CCCCCCCC(=O)C=CC1=CC=C(O)C(OC)=C1 AXMBOMODZLJDKX-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WHSIIJQOEGXWSN-UHFFFAOYSA-N 4-bromo-2-methoxyphenol Chemical compound COC1=CC(Br)=CC=C1O WHSIIJQOEGXWSN-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000234314 Zingiber Species 0.000 description 1
- 235000006886 Zingiber officinale Nutrition 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- JMFRWRFFLBVWSI-UHFFFAOYSA-N cis-coniferyl alcohol Natural products COC1=CC(C=CCO)=CC=C1O JMFRWRFFLBVWSI-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 235000008397 ginger Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000007210 heterogeneous catalysis Methods 0.000 description 1
- 238000009904 heterogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- RDIMTXDFGHNINN-UHFFFAOYSA-N panaxytriol Chemical compound CCCCCCCC(O)C(O)CC#CC#CC(O)C=C RDIMTXDFGHNINN-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- ZENOXNGFMSCLLL-UHFFFAOYSA-N vanillyl alcohol Chemical compound COC1=CC(CO)=CC=C1O ZENOXNGFMSCLLL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- 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
- C07C45/673—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 change of size of the carbon skeleton
- C07C45/676—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 change of size of the carbon skeleton by elimination of carboxyl groups
-
- 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
Abstract
The invention discloses a synthetic method of gingerol, which comprises the following synthetic steps: firstly, 4-chloromethyl-2-methoxyphenyl acetate is taken as a raw material, and is subjected to alkylation reaction with diethyl malonate under the action of alkali, and then is subjected to acylation reaction with octanoyl chloride under the action of alkali to generate 2- (4-acetoxyl-3-methoxyphenyl) -2-octanoyl diethyl malonate; secondly, the 2- (4-acetoxyl-3-methoxyphenyl) -2-octanoylmalonic acid diethyl ester is subjected to hydrolysis reaction in acid and water to obtain the target product, namely, the paradol. The synthesis method is simple, convenient to operate and free of special reaction conditions, and therefore the method is more suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a synthetic method of gingerol.
Background
Gingerol (6-Paradol), chemical name: 1- (4-hydroxy-3-methoxyphenyl) -3-decanone with molecular formula C17H26O3The CAS registry number: 277113-22-0. Gingerols were first isolated from the root of ginger. The gingerol has effects of reducing blood sugar and blood lipid, promoting metabolism, improving obesity constitution, and its toxicity and irritationAnd no related reports of any side effects exist until now, so that the paradol has a wide application prospect in the fields of health care products and functional food additives. The structure of gingerols is shown below.
At present, the synthesis method of gingerol is that in the Chinese invention patent CN201911202624, vanillin is used as a raw material, and the gingerol is prepared by condensation, hydrogenation reduction and Grignard reaction. Chinese patent CN201310532530 uses 4-bromo-2-methoxyphenol and 1-undecene-3-ketone as raw materials, prepares an ketene intermediate through condensation reaction, and finally obtains the gingerol through hydrogenation reduction. Patent US9272994 uses shogaol as raw material, and directly obtains shogaol by one-step hydrogenation. Chinese patent CN101018537A and european patent EP1800651a1 both relate to a two-step reaction process for synthesizing gingerol: firstly, dissolving vanillin and 2-nonanone in hexane and diethyl ether, and adding acetic acid and piperidine to obtain 1- (4-hydroxy-3-methoxyphenyl) dec-1-en-3-one; secondly, the prepared 1- (4-hydroxy-3-methoxyphenyl) dec-1-ene-3-ketone is hydrogenated and reduced in ethanol by adopting palladium carbon to obtain the zingerone. All of the above patents refer to hydrogenation reduction. In addition, there are four methods for preparing gingerol in the paper. In Eur.J.org.chem.2017(48), 7295-ketone 7299, 4-hydroxy-3-methoxy benzyl alcohol is used as an initial raw material, and the zingeronol is prepared through alkylation reaction, Ir/chitin heterogeneous catalysis and catalytic hydrogenation; the method also needs expensive heavy metal iridium as a catalyst. Med. chem.2017(60),9821-9837 uses vanillin as the starting material, and zingeronol is obtained by Aldol condensation and Pd/C catalysis and hydrogenation. In int.j.mol.sci.2014(15),3926-3951, vanillin is used as a starting material, and the gingerol is obtained by two-step Aldol condensation and catalytic hydrogenation. In PLOS One,2015,10(3),1-17, vanillin is used as an initial raw material, and the gingerol is prepared through alkylation reaction, Aldol condensation reaction, catalytic hydrogenation, condensation, deprotection, dehydration and catalytic hydrogenation. Thus, the existing processes essentially involve a route to hydrogenation reduction processes.
Disclosure of Invention
Therefore, the invention aims to provide a synthetic method of the paradol, which has the advantages of short synthetic route, simple and convenient synthesis, higher yield, suitability for large-scale industrial production and capability of overcoming the defects of the prior art.
The invention provides a synthetic method of gingerol, which comprises the following steps:
the synthesis step of the paradol comprises the following three steps:
the first step is as follows: 4-chloromethyl-2-methoxyphenyl acetate (namely a compound 1) is used as a raw material, and the 4-chloromethyl-2-methoxyphenyl acetate and diethyl malonate are subjected to alkylation reaction under the action of alkali to generate diethyl 2- (4-acetoxy-3-methoxyphenyl) malonate (namely a compound 2).
The second step is that: the compound diethyl 2- (4-acetoxyl-3-methoxyphenyl) malonate obtained in the first step and octanoyl chloride are subjected to acylation reaction under the action of alkali to generate diethyl 2- (4-acetoxyl-3-methoxyphenyl) -2-octanoyl malonate (namely, the compound 3).
The third step: and the compound 2- (4-acetoxyl-3-methoxyphenyl) -2-capryl diethyl malonate obtained in the second step is subjected to hydrolysis reaction in acid and water to remove carboxyl and acetyl, so that the target product, namely the compound 4, is obtained.
In the above reaction formula, Ac represents an acetyl group, and Et represents an ethyl group.
Preferably, the base in the first step is any one or more of potassium tert-butoxide, sodium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide, and is preferably sodium hydride.
Preferably, the mixed solution obtained in the reaction in the first step is directly used in the reaction in the second step without any treatment.
Preferably, the base in the second step is any one or more of potassium tert-butoxide, sodium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide, preferably sodium hydride.
Preferably, the mixed solution obtained in the second step is washed and the solvent is evaporated to dryness, and then the mixed solution can be directly used in the reaction in the third step, or the mixed solution obtained in the second step is added with water, extracted by an organic solvent, and the organic phase is evaporated to dryness, and then the solvent can be directly used in the reaction in the third step.
Preferably, the acid in the third step is any one or more of sulfuric acid, hydrochloric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, preferably both sulfuric acid and acetic acid.
Compared with the prior art, the invention has the following advantages:
the synthetic method takes 4-chloromethyl-2-methoxyphenyl acetate as a raw material, and obtains a target product through three steps of reactions, such as alkylation, acylation, hydrolysis and the like. The invention has the advantages of short production operation period, high equipment utilization rate, lower total cost and larger economic benefit.
Detailed Description
The reagents referred to in the following examples are not specifically described, but are commercial products and of chemical grade purity. In order to more clearly explain the technical problems and technical solutions solved by the present invention, the following embodiments further describe the present invention in detail. The specific embodiments described herein are merely illustrative of the invention and are not intended to be limiting.
Examples
Preparation of Compound 2
Into a 250mL three-necked flask, 2.6g of a solution was chargedDiethyl malonate and 40mL of N, N-dimethylformamide are stirred, the mixture is cooled in an ice-water bath, 0.66g of sodium hydride (60 percent of active ingredient) is added in batches, the temperature is controlled to be lower than 10 ℃, after the addition is finished, the mixture is continuously stirred for 15min, 3.2g of 4-chloromethyl-2-methoxyphenyl acetate solution dissolved in 10mL of N, N-dimethylformamide is dropwise added, the mixture is stirred for 2h at room temperature after the dropwise addition is finished, 80mL of water is added, 3X 50mL of ethyl acetate is used for extraction, organic phases are combined, the organic phases are washed by 100mL of salt water, and dried, concentrated and purified by column chromatography, and a developing agent: petroleum ether/ethyl acetate 4:1 gave 3.75g of a colorless oil in 74% yield.1HNMR(500MHz，CDCl3)δ6.93(d,J＝8.0Hz,1H,Ar-H),6.82(s,1H,Ar-H),6.78(d,J＝8.0Hz,1H,Ar-H),4.17(q,J＝7.1Hz,4H,O-CH2),3.85(t,J＝7.8Hz,1H,CH),3.80(s,3H,O-CH3),3.20(d,J＝7.8Hz,2H,Ar-CH2),2.29(s,3H,COCH3),1.22(t,J＝7.1Hz,6H,CH3)。13CNMR(125MHz，CDCl3)δ169.06,168.79,150.90,138.52,136.91,122.68,121.01,113.13,61.56,55.84,53.77,34.55,20.65,14.01.。
Preparation of Compound 3
In a 100mL three-necked flask, 3.20g of compound 2 was added, 20mL of N, N-dimethylformamide was added, stirring was performed, 0.38g of sodium hydride (60% as an active ingredient) was added in portions at room temperature, after the addition was completed, stirring was performed for 15min, then a solution of 1.70g of octanoyl chloride dissolved in 10mL of N, N-dimethylformamide was added dropwise, after the completion of the dropwise addition, reaction was performed at 80 ℃ for 4 hours, cooling to room temperature, 50mL of water was added, extraction was performed with 3X 50mL of ethyl acetate, the organic phases were combined, washed with 100mL of brine, dried with anhydrous sodium sulfate, concentrated, purified by column chromatography, and a developing agent: petroleum ether/ethyl acetate 10:1 gave 3.75g of a colourless oil in 85% yield. HRMS (ESI) calcd. for C25H36O8[M+H]+,465.2483；found 465.2220。
Preparation of gingerol 4
In a 500mL flask, 1.72g of compound 3, 6mL of acetic acid, 0.8mL of concentrated sulfuric acid and 4mL of water are added, stirred, heated under reflux for 4 hours, poured into 30mL of ice water, extracted with 20mL of ethyl acetate 3 times, the organic phases are combined, the organic phase is washed with 20mL of saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography, and a developing agent: ethyl acetate: petroleum ether (v/v) ═ 1:1, 0.78g of a pale yellow liquid was obtained in a yield of 76%. HRMS (ESI) calcd. for C17H26O3[M]+,278.1882；found 278.1226。
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any variations, equivalent alterations and modifications, etc., which are within the spirit and scope of the present invention are encompassed by the present invention.
Claims (4)
1. The synthetic method of the paradol is characterized by comprising the following steps:
firstly, carrying out alkylation reaction on 4-chloromethyl-2-methoxyphenyl acetate and diethyl malonate under the action of alkali, and after the reaction is completed, carrying out acylation reaction on the obtained product and octanoyl chloride under the action of alkali to obtain 2- (4-acetoxyl-3-methoxyphenyl) -2-octanoyl diethyl malonate; the reaction formula is as follows:
secondly, performing hydrolysis reaction on 2- (4-acetoxyl-3-methoxyphenyl) -2-capryl diethyl malonate in acid and water to remove carboxyl and acetyl to obtain gingerol; the reaction formula is as follows:
in the above reaction formula, Ac represents an acetyl group, and Et represents an ethyl group.
2. The synthesis method according to claim 1, wherein in the first step, the base is any one or more of potassium tert-butoxide, sodium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.
3. The synthesis method according to claim 1, wherein the mixed solution obtained from the reaction in the first step is washed and then the solvent is evaporated to dryness, and the mixed solution can be directly used in the reaction in the second step, or the mixed solution obtained from the reaction in the second step is added with water, extracted with an organic solvent, and the organic phase is evaporated to dryness and then the solvent can be directly used in the reaction in the third step.
4. The synthesis method according to claim 1, wherein in the second step, the acid is any one or more of sulfuric acid, hydrochloric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
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