CN113264850A - Synthetic method of nootropic ketonic A - Google Patents
Synthetic method of nootropic ketonic A Download PDFInfo
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- CN113264850A CN113264850A CN202110583027.8A CN202110583027A CN113264850A CN 113264850 A CN113264850 A CN 113264850A CN 202110583027 A CN202110583027 A CN 202110583027A CN 113264850 A CN113264850 A CN 113264850A
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- compound
- nootropic
- reaction
- ketone
- organic solvent
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- 230000001777 nootropic effect Effects 0.000 title claims abstract description 57
- 238000010189 synthetic method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- 150000002576 ketones Chemical class 0.000 claims abstract description 60
- 239000003960 organic solvent Substances 0.000 claims abstract description 37
- 229940125773 compound 10 Drugs 0.000 claims abstract description 25
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims abstract description 25
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims abstract description 25
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims abstract description 23
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- 230000002194 synthesizing effect Effects 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000001953 recrystallisation Methods 0.000 claims abstract description 17
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
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- 238000005804 alkylation reaction Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 239000011230 binding agent Substances 0.000 claims description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000011777 magnesium Substances 0.000 claims description 13
- 229910052749 magnesium Inorganic materials 0.000 claims description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
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- 239000003208 petroleum Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- XPBQQAHIVODAIC-UHFFFAOYSA-N 4-bromobutylbenzene Chemical compound BrCCCCC1=CC=CC=C1 XPBQQAHIVODAIC-UHFFFAOYSA-N 0.000 claims description 8
- LQNMGMMOHCDYPF-UHFFFAOYSA-N 4-iodobutylbenzene Chemical compound ICCCCC1=CC=CC=C1 LQNMGMMOHCDYPF-UHFFFAOYSA-N 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N DBU Substances C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000003747 Grignard reaction Methods 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- MOJORFVCTWDLTP-UHFFFAOYSA-N 4-fluorobutylbenzene Chemical compound FCCCCC1=CC=CC=C1 MOJORFVCTWDLTP-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- FLLZCZIHURYEQP-UHFFFAOYSA-N 4-chlorobutylbenzene Chemical compound ClCCCCC1=CC=CC=C1 FLLZCZIHURYEQP-UHFFFAOYSA-N 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000006052 Horner reaction Methods 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000005406 washing Methods 0.000 description 15
- 239000000126 substance Substances 0.000 description 12
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 7
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- TXELARZTKDBEKS-UHFFFAOYSA-N 1-(4'-hydroxy-3'-methoxyphenyl)-7-phenyl-3-heptanone Chemical compound C1=C(O)C(OC)=CC(CCC(=O)CCCCC=2C=CC=CC=2)=C1 TXELARZTKDBEKS-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- DKZBBWMURDFHNE-NSCUHMNNSA-N coniferyl aldehyde Chemical compound COC1=CC(\C=C\C=O)=CC=C1O DKZBBWMURDFHNE-NSCUHMNNSA-N 0.000 description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
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- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 2
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- PSFYBBLDOILMOZ-UHFFFAOYSA-M dichloromethane;tetrabutylazanium;fluoride Chemical compound [F-].ClCCl.CCCC[N+](CCCC)(CCCC)CCCC PSFYBBLDOILMOZ-UHFFFAOYSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic 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
- C07C45/68—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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Abstract
The invention provides a synthesis method of nootropic ketone A, belonging to the technical field of organic chemical synthesis. Is a preparation method of the nootropic ketonic A which is suitable for industrial production. According to the invention, vanillin is taken as an initial raw material, and a crude nootropic ketone is finally obtained through alkylation reaction, wittig-horner reaction, hydrolysis reaction, reduction reaction and various reactions in sequence, and then the high-purity nootropic ketone is prepared through organic solvent recrystallization. The method specifically comprises the steps of synthesizing a compound 8 through vanillin, synthesizing a compound 9 through the compound 8, synthesizing a compound 10 through the compound 9, synthesizing a compound 11 through the compound 10, finally synthesizing the nootropic ketone A through the compound 11, and then obtaining the high-purity nootropic ketone A through recrystallization. The synthesis method has the advantages of easily available raw materials, low cost, easy operation, good safety, less pollution, simple purification, easy quality control and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of nootropic ketone A.
Background
Nootropic ketone A (Yakuchinone-A), chemical name: 1- (4-hydroxy-3-methoxyphenyl) -7-phenyl-3-heptanone, CAS #:78954-23-1, is an active ingredient extracted from edible spice (Capsicum annuum). In the early days, Tiantang pepper was widely used in Africa as a medicinal and edible spice for dyspepsia, diarrhea, polyuria and stomachache. Recently, related researches at home and abroad show that the nootropic ketone A as one of main active ingredients in the Zanthoxylum piperitum has various beneficial biological activities, and on one hand, the compound can strongly inhibit the generation of biological prostaglandin, thereby having better anti-inflammatory and analgesic prospects. Meanwhile, the compound can effectively promote the apoptosis of skin cancer and human promyelocytic leucocyte (leukemia cell) by effectively inhibiting the expression of COX-2, NO synthetase and tumor necrosis factor amRNA in an organism; on the other hand, the nootropic ketone A is a natural product extracted from edible spices, has small toxic and side effects and irritation, and has no related report of any side effect at present; therefore, the nootropic ketone A has wider application and development prospect as a health-care product and a functional food additive.
At present, only the following two documents report the synthesis method of nootropic ketonic A:
Scheme 2 is shown in FIG. 14Bull. chem. Soc. Jpn,1989,62,1682-1684.
Route 2 is to obtain nootropic ketone A (1) by using nootropic ketone B (Yakuchin-B) as a starting material, using metal Se as a catalyst under an alkaline condition and carrying out high-pressure reduction under the action of CO. The starting material (nootropic ketone b) for this route is very expensive and not readily commercially available. Meanwhile, a metal catalyst Se used in the reaction is expensive and difficult to recover, and heavy metal residues are easily generated in the product, so that the quality of the product is greatly influenced. In addition, carbon monoxide (CO) used in the reaction process is a highly toxic and flammable gas, which brings great hidden trouble to safe production, and finally the reaction needs to be carried out under high pressure (30atm), which has very strict requirements on production equipment. Taken together, this route is not suitable for large-scale production.
Disclosure of Invention
In order to solve the technical problem of large-scale low-cost synthesis of the nootropic ketone A, the invention provides a method for synthesizing the nootropic ketone A by vanillin, and the specific synthetic route is as follows:
1. synthesis of compound 8 by vanillin: the compound 8 is obtained by taking vanillin as a raw material and carrying out alkylation reaction with TBDSCl in an organic solvent V under the action of an acid-binding agent II.
The acid-binding agent II comprises: sodium methoxide, sodium hydroxide, potassium hydroxide, anhydrous potassium carbonate, anhydrous sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, DBU, pyridine, potassium tert-butoxide, imidazole, preferably imidazole, anhydrous potassium carbonate;
the organic solvent V comprises: ethanol, methanol, dichloromethane, tetrahydrofuran, acetone, ethyl acetate, chloroform, acetonitrile, diethyl ether, methyl tert-butyl ether, N-dimethylformamide, preferably tetrahydrofuran, N-dimethylformamide.
The reaction conditions of the alkylation reaction between TBDSCl and an organic solvent V under the action of an acid-binding agent II are as follows: reacting for 1-24h at 0-100 ℃.
2. Compound 9 was synthesized via compound 8: the compound 9 is prepared by carrying out witig-horner reaction on a compound 8 and (2-methoxy (methyl) amino) -2-oxyethyl) diethyl phosphonate at the temperature of between 78 ℃ below zero and 0 ℃ under the action of an acid binding agent, and then recrystallizing in a recrystallization solvent II to obtain the compound 9, wherein the recrystallization solvent II is as follows: one or more of methanol, ethanol, ethyl acetate, petroleum ether, methyl tertiary butyl ether, acetone and diethyl ether in any proportion.
3. Compound 10 was synthesized from compound 9: the compound 10 is obtained by a hydrolysis reaction of a compound 9 in an organic solvent III under the action of tetrabutylammonium fluoride, wherein the organic solvent III comprises: methanol, ethanol, N-butanol, tetrahydrofuran, N, N-dimethylformamide and dichloromethane.
4. Compound 11 was synthesized from compound 10: the compound 11 is prepared from a compound 10 in an organic solvent II under the catalysis of Pd \ C and H2The organic solvent II is prepared by reduction reaction, and comprises: methanol, ethanol, propanol, ethyl acetate, petroleum ether, 1, 4-dioxane, acetone and methyl tertiary butyl ether.
5. Synthesis of nootropic ketone a via compound 11: the nootropic ketone A is prepared by carrying out Grignard reaction on a compound 11, 4-phenyl-1-halobutane and magnesium strips in an organic solvent I, and recrystallizing by using a recrystallization solvent to obtain the high-purity nootropic ketone A, wherein the organic solvent I comprises: THF, toluene, diethyl ether, 1, 4-dioxane and a THF/toluene mixed solution in any proportion; the 4-phenyl-1-halobutane comprises: 1-bromo-4-phenylbutane, 1-fluoro-4-phenylbutane, 1-chloro-4-phenylbutane, 1-iodo-4-phenylbutane; preferably 1-bromo-4-phenylbutane, 1-iodo-4-phenylbutane; the recrystallization solvent is: one or more of methanol, ethanol, ethyl acetate, acetone, petroleum ether, diethyl ether, methyl tertiary butyl ether, cyclohexane and n-hexane.
The preparation method of the compound 9 comprises the following steps: dissolving (2-methoxy (methyl) amino) -2-oxyethyl) diethyl phosphonate in an organic solvent IV, mixing with the acid-binding agent at a temperature of between 30 ℃ below zero and 30 ℃, reacting for 1h to 24h at a temperature of between 0 ℃ below zero and 100 ℃, dropwise adding an organic solvent IV solution of a compound 8 at a temperature of between 50 ℃ below zero and 50 ℃ after the reaction is finished, and finally, continuously reacting for 1h to 24h at a temperature of between 0 ℃ and 100 ℃ to obtain a compound 9; the organic solvent IV is as follows: anhydrous tetrahydrofuran, anhydrous n-butanol, anhydrous dichloromethane, anhydrous chloroform, diethyl ether, and anhydrous methyl tert-butyl ether.
Wherein the condition of the compound 9 dissolution hydrolysis reaction is that the reaction is carried out for 0.5h to 24h at the temperature of minus 10 ℃ to 80 ℃.
Wherein, the catalyst is catalyzed by Pd \ C in H2The conditions of the reduction reaction are as follows: adding Pd \ C into the solution of the compound 10 for catalysis, and introducing H2Reacting for 1-48 h at 0-100 deg.C under the condition of gas-to-reaction pressure of 0-30 atm.
Wherein the Grignard reaction conditions of the compound 11, the 4-phenyl-1-halobutane and the magnesium strip are as follows: firstly, mixing 4-phenyl-1-halobutane and magnesium strips, reacting for 1-10 h at 0-100 ℃, dropwise adding a solution of a compound 11 after the reaction is finished, and reacting for 1-24h at-10-100 ℃.
Advantageous effects
According to the invention, vanillin (7) which is cheap and easy to obtain is taken as an initial raw material, and a crude nootropic ketone is finally obtained through alkylation reaction, wittig-horner reaction, hydrolysis reaction, reduction reaction and various reactions in sequence, and then the high-purity nootropic ketone (1) is prepared through recrystallization of an organic solvent.
The invention adopts the vanillin (7) which is cheap and easy to obtain as the starting material in the aspect of synthetic route selection, so that the production cost is greatly reduced. Meanwhile, the invention firstly introduces a weineb amide structure into the compound 9 through wittig-horner reaction, and then carries out hydrogenation reaction under the catalysis of Pd \ C, and by utilizing the characteristic that amide is difficult to be catalytically hydrogenated, the phenomenon that double bonds and ketone carbonyl of alpha, beta-unsaturated ketone are simultaneously reduced under the same condition is effectively avoided, thereby avoiding the generation of byproducts to the maximum extent. In addition, the weineb amide structure related by the invention can be directly converted into ketone with high efficiency in the later-stage Grignard reaction, thereby avoiding a large amount of strong-oxidizing solid waste MnO2Is generated. In the aspect of product quality control, all reagent selections are effectively avoidedThe application of heavy metal, high-toxicity, explosive and other reagents is realized, and the intermediate in each step is purified through recrystallization, so that the defects of high cost, more solid waste, low production efficiency and the like caused by column chromatography purification in the currently reported method are effectively overcome. In conclusion, the invention reports an industrial synthesis route of the nootropic ketone A, which has the advantages of easily obtained raw materials, simple operation, safety, environmental protection, higher yield and simple purification, and makes the large-scale production of the high-quality nootropic ketone A possible.
The invention provides a novel preparation method of nootropic ketone A. Is a preparation method of the nootropic ketonic A which is suitable for industrial production. The invention obtains the high-purity nootropic ketone A by a recrystallization method. The preparation method has the advantages of easily available raw materials, low cost, easy operation, good safety, less pollution, simple purification, easy quality control and the like.
Drawings
FIG. 1: the invention synthesizes a general route diagram of nootropic ketone A by vanillin;
FIG. 2: the chemical structural formula of vanillin;
FIG. 3: the chemical structural formula of compound 8;
FIG. 4: the chemical structural formula of compound 9;
FIG. 5: the chemical structural formula of compound 10;
FIG. 6: the chemical structural formula of compound 11;
FIG. 7: the chemical structural formula of the nootropic ketone A;
FIG. 8: synthetic scheme for compound 8;
FIG. 9: synthetic scheme for compound 9;
FIG. 10: synthetic scheme for compound 10;
FIG. 11: synthetic scheme for compound 11;
FIG. 12: synthetic roadmaps for nootropic ketomes;
FIG. 13: synthetic pathway maps of reference scheme 1;
FIG. 14: synthetic pathway map of reference scheme 2.
Detailed Description
The reagents used in the following examples are commercially available, analytical reagents and chromatographic reagents unless otherwise specified. The following specific examples are provided to illustrate the invention in further detail in order to clearly explain the technical problems solved by the invention. The specific embodiments described herein are merely illustrative of the invention and are not intended to be limiting of the invention.
EXAMPLE 1
A method for synthesizing nootropic ketone A by vanillin comprises the following steps:
the preparation of compound 8, the synthetic route is shown in detail in FIG. 8.
Adding 1.0kg of vanillin 7(6.6mol,1.0e.q) and 5L of dichloromethane into a 10L reaction bottle in sequence, stirring at room temperature until the vanillin 7 and the dichloromethane are completely dissolved, adding 489.6g of imidazole (7.2mol,1.1e.q), stirring at room temperature for 8-15 min after mixing, adding 1.1kg of TBDSCl (7.2mol,1.1e.q), continuing to react at room temperature for 12h, monitoring by TLC, filtering after the reaction is finished, collecting filtrate, carrying out spin drying to obtain yellow oily matter, dissolving the obtained oily matter with 3L of dichloromethane, (washing a filter cake with a small amount of dichloromethane twice, combining the obtained solution with the dichloromethane solution), washing an organic phase with water twice, washing with saturated sodium chloride once, drying with anhydrous sodium sulfate, and carrying out spin drying to obtain 1.6kg of light yellow oily matter which is compound 8, wherein the yield is 94%.1H NMR(500MHz,CDCl3)δ9.86(s,1H),7.42(d,J＝1.6Hz,1H),7.39(dd,J＝1.6Hz,8.0 Hz,1H),6.98(d,J＝8.0Hz,1H),3.89(s,3H),1.03(s,9H),-0.22(s,6H)；13C NMR(125 MHz,CDCl3)δ190.85,151.65,151.33,131.01,126.11,120.72,110.25,55.41,25.60,18.49, -4.57；MS(ESI):m/z＝267.4[M+H]+.
The preparation and synthesis route of compound 9 is shown in fig. 8.
To a 10L reaction flask were added diethyl (2-methoxy (methyl) amino) -2-oxoethyl) phosphonate (1.6kg, 6.7mol,1.2e.q) and dry tetrahydrofuran (4L), cooled to 0 ℃ in an ice bath, potassium tert-butoxide (751.7g, 6.7mol,1.2e.q) was added in portions (internal temperature was controlled to 10 ℃ or less), after the addition was completed, the mixture was stirred at 0 ℃ for 1 hour, and then a tetrahydrofuran solution of Compound 8 (ca.3M THF,1.9L,5.6mol, 1) was slowly added dropwise.0e.q) (controlling the internal temperature below 5 ℃), adding, reacting at 0 ℃ for 1h, heating to room temperature, continuing to react for 12h, monitoring by TLC, pouring the reaction liquid into water after the reaction is finished, collecting an organic layer, extracting the water layer twice by ethyl acetate, and combining the organic layers. The organic phase was washed once with water, once with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to give a crude yellow oil, which was recrystallized (EA: PE ═ 1:5) to give 1.8kg of a white solid powder as compound 9 in 92% yield.1H NMR(500MHz,DMSO-d6)δ7.34 (d,J＝1.6Hz,1H),7.20(dd,J＝1.6Hz,8.1Hz,1H),7.0(d,J＝15.7Hz,1H),6.87(d,J＝ 8.1Hz,1H),3.85(s,3H),3.77(s,3H),3.24(s,3H),0.98(s,9H),0.16(s,6H)；13C NMR(125 MHz,DMSO-d6)δ166.12,150.66,146.14,142.36,128.86,121.51,120.54,114.40,111.91, 61.61,55.44,32.23,25.43,18.06,-4.80；MS(ESI):m/z＝352.5[M+H]+.
The preparation of compound 10, the synthetic route is shown in detail in FIG. 10.
To a 10L reaction flask were added compound 9(1.6kg,4.6mol,1.1e.q), THF 5L, tetrabutylammonium fluoride THF solution (3M,1.8L,5.5mol,1.2e.q) in that order, after the addition was completed, the reaction was carried out at room temperature for 30min, monitored by TLC, after the completion of the reaction, the pH was adjusted to 1 with 1M hydrochloric acid, and THF was removed under reduced pressure. The resulting solution was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated brine, respectively, and the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 1.1kg of a pale yellow oily substance, which was the compound 10 with a yield of 98%.1H NMR(500MHz,CDCl3)δ(d,J＝15.7Hz,1H),7.08(dd,J＝1.4Hz,8.2Hz,1H),6.99(s, 1H),6.89(d,J＝8.2Hz,6.83(d,J＝15.7Hz),1H),3.86(s,3H),3.72(s,3H),3.27(s,3H)；13C NMR(125MHz,CDCl3)δ167.30,147.85,146.89,143.79,127.37,122.20,114.90, 112.76,110.28,61.68,55.85,32.44.MS(ESI):m/z＝238.2[M+H]+.
The preparation of compound 11, the synthetic route is shown in detail in FIG. 11.
To a 10L reaction flask were added compound 10(1.0kg,4.2mol), Pd/C (50g), and methanol (4L) in that order. After the addition, stirring the mixture in hydrogen for 3 hours at room temperature and normal pressure, TLC detection, after the reaction, suction filtration is carried out, the filtrate is collected and spin-dried to obtain 964.6g of light yellow oily matter with the yield of 96%.1H NMR(500MHz,CDCl3)δ6.82(d,J＝7.9Hz,1H),6.71(m, 2H),5.72(br,1H),3.86(s,3H),3.60(s,3H),3.18(s,3H),2.88(t,J＝7.4Hz,2H),2.71(t,J ＝7.4Hz,2H)；13C NMR(125MHz,CDCl3)δ207.56,146.54,144.05,133.31,120.92,114.44, 111.33,110.01,61.32,55.91,34.18,30.51；MS(ESI):m/z＝240.1[M+H]+.
The preparation and the synthetic route of the nootropic ketone A (1) are shown in a figure 12.
788.5g of 1-bromo-4-phenylbutane (3.7mol,1.0e.q), 97g of magnesium strips (4.1mol,1.1e.q) and 3L of dried tetrahydrofuran are sequentially added into a 10L reaction bottle, after the addition is finished, the reaction is carried out for 1h at 40 ℃ under the protection of argon, after the reaction is finished, the reaction liquid is cooled to 0 ℃,1.9L of 2M tetrahydrofuran solution (3.7mol,1.0e.q) of compound 11 is slowly added, after the addition is finished, the reaction liquid is heated to room temperature to continue reacting for 1h, TLC detection is carried out, after the reaction is finished, the reaction liquid is quenched by saturated ammonium chloride aqueous solution (1L), and then pH is adjusted to 1 by 1M dilute hydrochloric acid solution. Pouring the obtained solution into water, extracting the water phase with ethyl acetate for three times, combining organic phases, drying the obtained organic phases with anhydrous sodium sulfate, filtering and spin-drying to obtain a yellow oily crude product, and recrystallizing the obtained crude product with cyclohexane/petroleum ether (3/1) to obtain 888.8g of white waxy solid, namely the nootropic ketone A, wherein the yield is 77%.1H NMR(500MHz,CDCl3)δ7.32(t,J＝7.4Hz,2H),7.24-7.19(m,3H),6.87(d,J＝ 7.9Hz,1H),6.72(d,J＝7.9Hz,1H),6.70(d,J＝8.0Hz,1H),5.56(s,1H),3.90(s,3H),2.87 (t,J＝7.4Hz,2H),2.72(t,J＝7.4Hz,2H),2.65(t,J＝7.0Hz,2H),2.44(t,J＝7.0Hz,2H), 1.68-1.65(m,4H)；13C NMR(125MHz,CDCl3)δ210.18,146.42,143.94,142.16,133.06, 128.35,128.30,125.75,120.78,114.35,111.11,55.88,44.60,42.90,35.71,3094,29.55, 23.41；MS(ESI):m/z＝311.4[M-H]-.
EXAMPLE 2
A method for synthesizing nootropic ketone A by vanillin comprises the following steps:
preparation of compound 8: adding 1.0kg of vanillin and 5L of dichloromethane into a reaction bottle in sequence, stirring at 80 ℃ until the vanillin and the 5L of dichloromethane are completely dissolved, adding 2mol of an acid-binding agent, stirring at room temperature for 8-15 min after mixing is completed, carrying out 1.1kg of TBDSC, continuing reaction at 100 ℃ for 1h, filtering after the reaction is completed, collecting filtrate, carrying out spin drying to obtain a yellow oily substance, dissolving the obtained oily substance with dichloromethane, washing an organic phase twice with water, washing with saturated sodium chloride once, drying with anhydrous sodium sulfate, and carrying out spin drying to obtain a compound 8.
Preparation of compound 9: adding 1.6kg of (2-methoxy (methyl) amino) -2-oxyethyl) diethyl phosphonate and 4L of anhydrous dichloromethane into a reaction bottle respectively, cooling to 0 ℃, adding 2mol of anhydrous potassium carbonate, stirring at 0 ℃ for 1h, slowly dropwise adding 1.9L of dichloromethane solution of a 3M compound 8, reacting at 0 ℃ for 1h, finally rising to 50, continuing to react for 12h, pouring the reaction solution into water after the reaction is finished, collecting an organic layer, extracting the water layer twice by using ethyl acetate, and combining organic phases. Washing the obtained organic phase once by water, washing once by saturated sodium chloride, drying by anhydrous sodium sulfate, and spin-drying to obtain a crude compound 9, and recrystallizing the crude compound 9 by ethyl acetate to obtain the high-purity compound 9.
Preparation of compound 10: 1.8kg of compound 9, 5L of dichloromethane and 2L of 3M tetrabutylammonium fluoride dichloromethane solution were added in this order to a reaction flask and hydrolyzed at-10 ℃ for 24 hours, the resulting solution was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated brine, respectively, and the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 10.
Preparation of compound 11: to the reaction flask were added 1.5kg of Compound 10, 20g Pd/C and 4L of petroleum ether in this order. Introduction of H2Reacting for 48h under the conditions that the reaction pressure is 30atm and the temperature is 0 ℃. And after the reaction is finished, carrying out suction filtration, collecting filtrate, and carrying out spin drying to obtain the compound 11.
Preparing nootropic ketone A: mixing 1-iodo-4-phenylbutane and magnesium strips with 1, 4-dioxane to prepare a 1, 4-dioxane solution with a final concentration of 3.7mol/L of 1-fluoro-4-phenylbutane and a final concentration of 4.1mol/L of magnesium, reacting at 100 ℃ for 1hh under the protection of helium, dropwise adding 1.9L of 1mol/L compound 111 and 4-dioxane solution after the reaction is finished, reacting at-10 ℃ for 24h, quenching the reaction liquid with a saturated ammonium chloride aqueous solution after the reaction is finished, and adjusting the Ph to 0.8 by using 1M dilute hydrochloric acid solution. Pouring the obtained solution into water, extracting the water phase with ethyl acetate for three times, combining organic phases, and sequentially drying the obtained organic phases with anhydrous sodium sulfate, filtering and spin-drying to obtain the nootropic ketone A.
EXAMPLE 3
A method for synthesizing nootropic ketone A by vanillin comprises the following steps:
preparation of compound 8: adding 1.0kg of vanillin and 5L of dichloromethane into a reaction bottle in sequence, stirring at 0 ℃ until the vanillin and the 5L of dichloromethane are completely dissolved, adding 2mol of an acid-binding agent, stirring at room temperature for 8-15 min after mixing is completed, carrying out 1.1kg of TBDSC, continuing reaction at 0 ℃ for 24h, filtering after the reaction is completed, collecting filtrate, carrying out spin drying to obtain a yellow oily substance, dissolving the obtained oily substance with dichloromethane, washing an organic phase twice with water, washing with saturated sodium chloride once, drying with anhydrous sodium sulfate, and carrying out spin drying to obtain a compound 8.
Preparation of compound 9: adding 1.6kg of (2-methoxy (methyl) amino) -2-oxyethyl) phosphonic acid diethyl ester and 4L of anhydrous n-butanol into a reaction bottle respectively, cooling to 0 ℃, adding 2mol of sodium methoxide, stirring at 0 ℃ for 1h, slowly dropwise adding 1.9L of 3M compound 8 n-butanol solution, reacting at 0 ℃ for 1h, finally rising to 50, continuing to react for 12h, pouring the reaction solution into water after the reaction is finished, collecting an organic layer, extracting the water layer twice with ethyl acetate, and combining organic phases. Washing the obtained organic phase once by water, washing once by saturated sodium chloride, drying by anhydrous sodium sulfate, and spin-drying to obtain a crude compound 9, and recrystallizing the crude compound 9 by petroleum ether to obtain the high-purity compound 9.
Preparation of compound 10: 1.8kg of compound 9, 5L of tetrahydrofuran and 2L of 3M tetrabutylammonium fluoride tetrahydrofuran solution were sequentially added to a reaction flask, and hydrolyzed at 80 ℃ for 0.5 hr, and the resulting solution was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated brine, respectively, and the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 10.
Preparation of compound 11: to the reaction flask were added 1.5kg of Compound 10, 20g Pd/C and 4L ethyl acetate in that order. Introduction of H2Reacting for 1h under the conditions that the reaction pressure is 0atm and the temperature is 100 ℃. And after the reaction is finished, carrying out suction filtration, collecting filtrate, and carrying out spin drying to obtain the compound 11.
Preparing nootropic ketone A: mixing 1-bromo-4-phenylbutane and magnesium strips with THF to prepare a THF solution with a final concentration of 1-fluoro-4-phenylbutane of 3.7mol/L and a final concentration of magnesium of 4.1mol/L, reacting at 0 ℃ for 10 hours under the protection of inert gas, dropwise adding 1.5L of 3mol/L compound 11THF solution after the reaction is finished, reacting at 100 ℃ for 1 hour, quenching the reaction liquid with saturated ammonium chloride aqueous solution after the reaction is finished, and adjusting the pH to 1.5 with 1M dilute hydrochloric acid solution. Pouring the obtained solution into water, extracting the water phase with ethyl acetate for three times, combining organic phases, and sequentially drying the obtained organic phases with anhydrous sodium sulfate, filtering and spin-drying to obtain the nootropic ketone A.
EXAMPLE 4
A method for synthesizing nootropic ketone A by vanillin comprises the following steps:
preparation of compound 8: adding 1.0kg of vanillin and 5L of dichloromethane into a reaction bottle in sequence, stirring at 0-100 ℃ until the vanillin, the dichloromethane and the dichloromethane are completely dissolved, adding 2mol of an acid binding agent, stirring at room temperature for 8-15 min after mixing, continuing to react at 0-100 ℃ for 1-24h by 1.1kg of TBDSC, filtering after the reaction is finished, collecting filtrate, carrying out spin drying to obtain yellow oily matter, dissolving the obtained oily matter by dichloromethane, washing the organic phase twice by water, washing by saturated sodium chloride once, drying by anhydrous sodium sulfate, and carrying out spin drying to obtain the compound 8.
Preparation of compound 9: adding 1.6kg of (2-methoxy (methyl) amino) -2-oxyethyl) diethyl phosphonate and 4L of anhydrous n-butyl alcohol into a reaction bottle respectively, cooling to a temperature of-30 ℃, adding 2mol of an acid binding agent, reacting for 1-24h at the temperature of 0-100 ℃, slowly dropwise adding 1.9L of organic solvent IV solution of 3M compound 8, continuing to react for 1-24h at the temperature of 0-100 ℃, pouring the reaction liquid into water after the reaction is finished, collecting an organic layer, extracting a water layer twice by using a recrystallization solvent II, and combining organic phases. Washing the obtained organic phase once by water, washing once by saturated sodium chloride, drying by anhydrous sodium sulfate and spin-drying to obtain the compound 9.
The organic solvent IV is as follows: anhydrous tetrahydrofuran, anhydrous n-butanol, anhydrous dichloromethane, anhydrous chloroform, diethyl ether, and anhydrous methyl tert-butyl ether.
The acid-binding agent comprises: sodium methoxide, potassium tert-butoxide, anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydride and DBU in any proportion.
The recrystallization solvent II is as follows: one or more of methanol, ethanol, ethyl acetate, petroleum ether, methyl tertiary butyl ether, acetone and diethyl ether in any proportion.
Preparation of compound 10: 1.8kg of compound 9, 5L of organic solvent III and 2L of 3M solution of tetrabutylammonium fluoride in organic solvent III are added into a reaction flask in sequence, hydrolysis reaction is carried out for 0.5h-24h at-10 ℃ to 80 ℃, the obtained solution is extracted three times by ethyl acetate, and the organic phases are combined. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated brine, respectively, and the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 10.
The organic solvent III comprises: methanol, ethanol, N-butanol, tetrahydrofuran, N, N-dimethylformamide and dichloromethane.
Preparation of compound 11: the compound 10, Pd/C and the organic solvent II were added to the reaction flask in this order. Introduction of H2Gas reacts for 1 to 48 hours under the conditions that the reaction pressure is 0 to 30atm and the temperature is 0 to 100 ℃. And after the reaction is finished, carrying out suction filtration, collecting filtrate, and carrying out spin drying to obtain the compound 11.
The organic solvent II comprises: methanol, ethanol, propanol, ethyl acetate, petroleum ether, 1, 4-dioxane, acetone and methyl tertiary butyl ether.
Preparing nootropic ketone A: mixing 4-phenyl-1-halobutane and magnesium strips with an organic solvent I to prepare an organic solvent I solution of 4-phenyl-1-halobutane and magnesium, reacting at 0-100 ℃ for 1-10 h under the protection of inert gas, dropwise adding the organic solvent I solution of a compound 11 after the reaction is finished, reacting at-10-100 ℃ for 1-24h, quenching the reaction solution with a saturated ammonium chloride aqueous solution after the reaction is finished, and adjusting the pH to 1. Pouring the obtained solution into water, extracting the water phase for three times by using a recrystallization solvent, combining organic phases, and sequentially drying, filtering and spin-drying the obtained organic phases by using anhydrous sodium sulfate to obtain the nootropic ketone A.
Wherein, the organic solvent I comprises: THF, toluene, diethyl ether, 1, 4-dioxane and a THF/toluene mixed solution in any proportion; the 4-phenyl-1-halobutane comprises: 1-bromo-4-phenylbutane, 1-fluoro-4-phenylbutane, 1-chloro-4-phenylbutane, 1-iodo-4-phenylbutane; preferably 1-bromo-4-phenylbutane, 1-iodo-4-phenylbutane; the recrystallization solvent includes: one or more of methanol, ethanol, ethyl acetate, acetone, petroleum ether, diethyl ether, methyl tertiary butyl ether, cyclohexane and n-hexane.
Claims (10)
1. A synthetic method of nootropic ketone A is characterized in that: the nootropic ketone A is prepared by carrying out Grignard reaction on a compound 11, 4-phenyl-1-halobutane and magnesium strips in an organic solvent I, and recrystallizing by using a recrystallization solvent to obtain the high-purity nootropic ketone A, wherein the structural formula of the compound 11 is as follows:
the organic solvent I comprises: THF, toluene, diethyl ether, 1, 4-dioxane and a THF/toluene mixed solution in any proportion;
the 4-phenyl-1-halobutane comprises: 1-bromo-4-phenylbutane, 1-fluoro-4-phenylbutane, 1-chloro-4-phenylbutane, 1-iodo-4-phenylbutane; preferably 1-bromo-4-phenylbutane, 1-iodo-4-phenylbutane;
the recrystallization solvent is: one or more of methanol, ethanol, ethyl acetate, acetone, petroleum ether, diethyl ether, methyl tertiary butyl ether, cyclohexane and n-hexane.
2. The method for synthesizing nootropic ketone A as claimed in claim 1, wherein: the compound 11 is prepared from a compound 10 in an organic solvent II under the catalysis of Pd \ C and H2The compound is prepared by reduction reaction, wherein the structural formula of the compound 10 is as follows:
the organic solvent II comprises: methanol, ethanol, propanol, ethyl acetate, petroleum ether, 1, 4-dioxane, acetone and methyl tertiary butyl ether.
3. The method for synthesizing nootropic ketone A as claimed in claim 2, wherein: the compound 10 is obtained by a hydrolysis reaction of a compound 9 in an organic solvent III under the action of tetrabutylammonium fluoride, wherein the structural formula of the compound 9 is as follows:
the organic solvent III comprises: methanol, ethanol, N-butanol, tetrahydrofuran, N, N-dimethylformamide and dichloromethane.
4. The method for synthesizing nootropic ketone A as claimed in claim 3, wherein: the compound 9 is prepared by performing witig-horner reaction on a compound 8 and (2-methoxy (methyl) amino) -2-oxyethyl) diethyl phosphonate at-78-0 ℃ under the action of an acid binding agent, and then recrystallizing in a recrystallization solvent II to obtain the compound 9, wherein the structural formula of the compound 8 is as follows:
the acid-binding agent comprises: one or more mixed solvents in any proportion of sodium methoxide, potassium tert-butoxide, anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydride and DBU;
the recrystallization solvent II is as follows: one or more of methanol, ethanol, ethyl acetate, petroleum ether, methyl tertiary butyl ether, acetone and diethyl ether in any proportion.
5. The method for synthesizing nootropic ketone A as claimed in claim 4, wherein: the compound 8 is prepared by taking vanillin as a raw material and carrying out alkylation reaction with TBDSCl in an organic solvent V under the action of an acid-binding agent II, wherein the vanillin has the following structural formula:
the acid-binding agent II comprises: sodium methoxide, sodium hydroxide, potassium hydroxide, anhydrous potassium carbonate, anhydrous sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, DBU, pyridine, potassium tert-butoxide, imidazole, preferably imidazole, anhydrous potassium carbonate;
the organic solvent V comprises: ethanol, methanol, dichloromethane, tetrahydrofuran, acetone, ethyl acetate, chloroform, acetonitrile, diethyl ether, methyl tert-butyl ether, N-dimethylformamide, preferably tetrahydrofuran, N-dimethylformamide.
6. The method for synthesizing nootropic ketone A as claimed in claim 5, wherein: the reaction conditions of the alkylation reaction between TBDSCl and an organic solvent V under the action of an acid-binding agent II are as follows: reacting for 1-24h at 0-100 ℃; the acid-binding agent II comprises: sodium methoxide, potassium tert-butoxide, anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydride and DBU in any proportion.
7. The method for synthesizing nootropic ketone A as claimed in claim 4, wherein: the preparation method of the compound 9 comprises the following steps: dissolving (2-methoxy (methyl) amino) -2-oxyethyl) diethyl phosphonate in an organic solvent IV, mixing with the acid-binding agent at-30 ℃, reacting for 1-24h at 0-100 ℃, dropwise adding an organic solvent IV solution of a compound 8 at-50 ℃ after the reaction is finished, and finally, continuously reacting for 1-24h at 0-100 ℃ to obtain a compound 9;
the organic solvent IV is as follows: anhydrous tetrahydrofuran, anhydrous n-butanol, anhydrous dichloromethane, anhydrous chloroform, diethyl ether, and anhydrous methyl tert-butyl ether.
8. The method for synthesizing nootropic ketone A as claimed in claim 3, wherein: the condition of the compound 9 dissolving hydrolysis reaction is that the reaction is carried out for 0.5h-24h at the temperature of-10 ℃ to 80 ℃.
9. The method for synthesizing nootropic ketone A as claimed in claim 2, wherein: under the catalysis of Pd \ C and H2The conditions of the reduction reaction are as follows: adding Pd \ C into the solution of the compound 10 for catalysis, and introducing H2Reacting for 1-48 h at 0-100 ℃ until the reaction pressure is 0-30 atm.
10. The method for synthesizing nootropic ketone A as claimed in claim 1, wherein: the Grignard reaction conditions of the compound 11, the 4-phenyl-1-halobutane and the magnesium strip are as follows: firstly, mixing 4-phenyl-1-halobutane and magnesium strips, reacting for 1 h-10 h at 0-100 ℃, dropwise adding a solution of a compound 11 after the reaction is finished, and reacting for 1h-24h at-10-100 ℃.
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|---|---|---|---|---|
| CN116602944A (en) * | 2023-06-09 | 2023-08-18 | 华南农业大学 | Application of alpinia oxyphylla alcohol or alpinia oxyphylla ketone A in preparation of medicines for preventing or assisting in treating inflammation |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567279A (en) * | 1984-12-13 | 1986-01-28 | Usv Pharmaceutical Corp. | Diarylhydroxy alkanones and alkenones antiallergy agents |
| US5266344A (en) * | 1988-08-12 | 1993-11-30 | Kabushiki Kaisha Kobe Seiko Sho | Method for making tetrahydrocurcumin and a substance containing the antioxidative substance tetrahydrocurcumin |
| CN106831383A (en) * | 2016-12-28 | 2017-06-13 | 中国科学院成都生物研究所 | Diarylheptanoids |
| CN109081775A (en) * | 2018-08-17 | 2018-12-25 | 中国科学院西北高原生物研究所 | The directional separation and purification method of Diarylheptanoids in Tang Gute kiss-me |
| CN110937985A (en) * | 2019-11-29 | 2020-03-31 | 许昌远志生物科技有限公司 | Synthetic method of paradol |
-
2021
- 2021-05-27 CN CN202110583027.8A patent/CN113264850A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567279A (en) * | 1984-12-13 | 1986-01-28 | Usv Pharmaceutical Corp. | Diarylhydroxy alkanones and alkenones antiallergy agents |
| US5266344A (en) * | 1988-08-12 | 1993-11-30 | Kabushiki Kaisha Kobe Seiko Sho | Method for making tetrahydrocurcumin and a substance containing the antioxidative substance tetrahydrocurcumin |
| CN106831383A (en) * | 2016-12-28 | 2017-06-13 | 中国科学院成都生物研究所 | Diarylheptanoids |
| CN109081775A (en) * | 2018-08-17 | 2018-12-25 | 中国科学院西北高原生物研究所 | The directional separation and purification method of Diarylheptanoids in Tang Gute kiss-me |
| CN110937985A (en) * | 2019-11-29 | 2020-03-31 | 许昌远志生物科技有限公司 | Synthetic method of paradol |
Non-Patent Citations (2)
| Title |
|---|
| HWA JIN LEE等: "Suppression of Imducible Nitric Oxide Synthase Expression by Yakuchinones and Their Analogues" * |
| XIANG SHI 等: "Concise and Efficient Synthesis of [6]-Paradol" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116602944A (en) * | 2023-06-09 | 2023-08-18 | 华南农业大学 | Application of alpinia oxyphylla alcohol or alpinia oxyphylla ketone A in preparation of medicines for preventing or assisting in treating inflammation |
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