CN117304093A - Piperidone alkaloid and analogues, synthesis method and application thereof - Google Patents
Piperidone alkaloid and analogues, synthesis method and application thereof Download PDFInfo
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- CN117304093A CN117304093A CN202311247617.9A CN202311247617A CN117304093A CN 117304093 A CN117304093 A CN 117304093A CN 202311247617 A CN202311247617 A CN 202311247617A CN 117304093 A CN117304093 A CN 117304093A
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- China
- Prior art keywords
- piperidine
- methoxybenzyl
- piperidone
- alkaloid
- ethyl acetate
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 34
- -1 p-methoxybenzyl Chemical group 0.000 claims abstract description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 22
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 claims abstract description 20
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011630 iodine Substances 0.000 claims abstract description 16
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 16
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 claims abstract description 13
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims abstract description 12
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000003335 secondary amines Chemical class 0.000 claims abstract description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012312 sodium hydride Substances 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 239000000758 substrate Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
- 239000000047 product Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- DGSQXYGFDGFQLQ-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]piperidine Chemical compound C1=CC(OC)=CC=C1CN1CCCCC1 DGSQXYGFDGFQLQ-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 20
- JQXZUJUIBJZRAJ-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]piperidine-2,3-dione Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C(=O)CCC1 JQXZUJUIBJZRAJ-UHFFFAOYSA-N 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 13
- 238000010791 quenching Methods 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 230000000171 quenching effect Effects 0.000 claims description 10
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 12
- 238000010828 elution Methods 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- 239000001257 hydrogen Substances 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract 1
- 229910002651 NO3 Inorganic materials 0.000 abstract 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 238000001228 spectrum Methods 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229930013930 alkaloid Natural products 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- 229930000044 secondary metabolite Natural products 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- 229940119568 Inducible nitric oxide synthase inhibitor Drugs 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003647 acryloyl group Chemical class O=C([*])C([H])=C([H])[H] 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000000871 hypocholesterolemic effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 231100001224 moderate toxicity Toxicity 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 229940124560 neurologic drug Drugs 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a synthesis method of active piperidone alkaloid, which adopts raw material piperidine as a substrate, reacts with p-methoxybenzyl chloride under the condition of N, N-diisopropylethylamine to protect secondary amine, avoids subsequent side reaction of sodium hydride and hydrogen on the secondary amine, is oxidized under the condition of iodine simple substance and iodobenzene diacetic acid, then reacts with triethylphosphonoacetate to obtain alpha, beta unsaturated ester, then removes protection of p-methoxybenzyl with ammonium ceric nitrate mildly and efficiently, finally reduces the ester into alcohol with diisobutyl aluminum hydride, finally obtains piperidone alkaloid or analogues thereof through five steps of reaction.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to piperidone alkaloid and analogues thereof, a synthesis method and application.
Background
Marine organisms account for about 87% of the total biomass of the earth, and are widely biologically active due to the existence of high-salt, high-pressure, anoxic and photophobic living environments in the ocean and the strong competitive pressure of the marine organisms, so that the ocean is a huge natural medicine treasury, particularly the alkaloid which is a secondary metabolite with alkalinity containing amide groups and other complex carbon skeleton ring structures and synthesized from different amino acids or direct derivatives thereof.
Piperidine, chemical name azacyclohexane, piperidine. Unlike pyridine, piperidine is a non-aromatic, saturated six-membered nitrogen heterocyclic compound; the black pepper-flavored liquid is colorless liquid with a boiling point of 106 ℃, can be dissolved in solvents such as water, ethanol, diethyl ether and the like, has alkalinity far greater than that of pyridine, is strong base, has corrosion and moderate toxicity, forms salt with acid, can be burnt by explosion caused by open fire and high heat energy, can react with oxidant strongly, and needs to be stored in a cool and ventilated place. Piperidine is an important azacyclic organic intermediate, only small-scale production is performed in China at present, and the main synthetic route is that pyridine is used as a raw material to be hydrogenated in the presence of a platinum oxide or Raney Ni catalyst; the pyridine is also reported to be prepared by electrolytic reduction.
Piperidones and derivatives thereof are very important piperidine homologs, and the activity of carbonyl groups and methylene groups at the ortho positions of the piperidones can be utilized to initiate a plurality of organic reactions, so that a plurality of practical medical, pesticide and chemical intermediates are derived. In particular to N-substituted-4-piperidone compounds which are important synthesis intermediates for preparing various alkaloids and medicines and play an increasingly important role in medicine synthesis. The derivatives thereof have been found to have antidepressant, antiarrhythmic, antithrombotic, spasmolytic, sedative and hypocholesterolemic activities, and in addition, the N-substituted-4-piperidones are important intermediates of many neurologic drugs, and are widely used for analgesia, antiarrhythmic, M-series muscarinic impedance agents, central nervous system 5HT1A receptor impedance agents and the like at present, such as the first analgesic drug of pethidine (pethidine) synthesized in 1939, and the tranexamic analgesic drugs widely used at present with high therapeutic indexes and good safety; in addition, jonathan et al synthesized a series of 3, 5-di (arylene) -4-piperidone and its N-substituted acryloyl derivatives, and biological activity tests showed that many of these compounds had cytotoxic activity against murine leukemia cell P388 and human leukemia cell L1210, and human Molt 4/C8 and CEM tumors, with the mechanism of action of inhibiting biosynthesis of tumor cell DNA, RNA and proteins, and hopefully screening them for highly potent anticancer drugs.
Disclosure of Invention
The invention provides a synthesis method of an active piperidone alkaloid, which is DysidoneA, and the structure of the active piperidone alkaloid is shown as a formula (I):
the preparation method comprises the following steps:
protection of S1 secondary amine: piperidine is taken as a substrate, and reacts with p-methoxybenzyl chloride in the presence of N, N-diisopropylethylamine to obtain 1- (4-methoxybenzyl) piperidine;
oxidation of S2 piperidone derivatives: reacting the product 1- (4-methoxybenzyl) piperidine obtained in the step S1 with iodine simple substance and iodobenzene diacetic acid to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione;
connection of S3C-C bond: reacting the product 1- (4-methoxybenzyl) piperidine-2, 3-dione obtained in S2 with triethylphosphonoacetate to obtain (Z) -2- (1- (4-methoxybenzyl) -2-oxopiperidin-3-ylidene) acetic acid ethyl ester;
s4 removal of methoxybenzyl: reacting the (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate obtained in the step S3 with ceric ammonium nitrate, and removing the protection treatment of the p-methoxybenzyl group to obtain (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate;
reduction of S5 ester group: reacting the (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate obtained in the step S4 with diisobutyl aluminum hydride to obtain a final product (Z) -3- (2-hydroxyethylidene) piperidin-2-one;
further, in S1, the mol ratio of the p-methoxybenzyl chloride, the piperidine and the N, N-diisopropylethylamine is 0.5-2:0.5-2:1-1.8; further, in S1, the mol ratio of the p-methoxybenzyl chloride, the piperidine and the N, N-diisopropylethylamine is 1.1:1.0:1.5;
further, in S1, the reaction is completed in solvent dichloromethane (i.e., DCM);
in the step S1, the p-methoxybenzyl chloride is added dropwise; further, in S1, the dropping temperature is 0 ℃;
further, the specific step S1 includes the following steps: dissolving piperidine and N, N-diisopropylethylamine in dichloromethane, dropwise adding p-methoxybenzyl chloride under ice bath condition, then reacting at room temperature overnight, and purifying the obtained reaction liquid after the reaction is finished to obtain 1- (4-methoxybenzyl) piperidine;
in S1, the purification refers to washing the obtained reaction liquid with saturated saline solution, extracting the water layer with dichloromethane three times, merging organic phases, drying, and separating and purifying by column chromatography under the condition that the volume ratio of petroleum ether to ethyl acetate is 15:1 to obtain a target product;
further, in S2, the product 1- (4-methoxybenzyl) piperidine, iodobenzene diacetic acid and iodine in S1 are dissolved in dry tetrahydrofuran, and the molar ratio of the 1- (4-methoxybenzyl) piperidine, the iodobenzene diacetic acid and the iodine is as follows: 0.5-2:1.0-3.0:1.0-3.0, stirring for 30-60 min, adding iodobenzene diacetic acid with the same molar weight as 1- (4-methoxybenzyl) piperidine, continuing to quench for 10-15 h by using saturated sodium thiosulfate solution, and purifying the obtained reaction solution after quenching reaction to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione; preferably, the molar ratio of the 1- (4-methoxybenzyl) piperidine to the iodobenzene diacetic acid to the iodine is as follows: 1.0:2.0:2.0; preferably, the stirring time is 50min; preferably, the stirring is continued for 12 hours;
dissolving the product 1- (4-methoxybenzyl) piperidine, iodobenzene diacetic acid and iodine in S1 into dry tetrahydrofuran, wherein the molar ratio of the 1- (4-methoxybenzyl) piperidine to the iodobenzene diacetic acid to the iodine is as follows: 0.5-2:1.0-3.0:1.0-3.0, stirring for a period of time, adding iodobenzene diacetic acid with the same molar weight as 1- (4-methoxybenzyl) piperidine, continuously reacting for a period of time, quenching with saturated sodium thiosulfate solution, and purifying the obtained reaction solution after quenching reaction to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione; preferably, in S2, the molar ratio of 1- (4-methoxybenzyl) piperidine, iodobenzene diacetic acid and iodine is: 1.0:2.0:2.0;
in S2, extracting with ethyl acetate and saturated saline for three times, mixing organic phases, drying, separating and purifying by column chromatography under the condition that the volume ratio of petroleum ether to ethyl acetate is 5:1 to obtain the target product;
further, in S3, the reaction mole ratio of the product 1- (4-methoxybenzyl) piperidine-2, 3-dione and triethyl phosphonoacetate obtained in S2 is 0.8-1.5:1-2; preferably, the reaction mole ratio of the product 1- (4-methoxybenzyl) piperidine-2, 3-dione and triethyl phosphonoacetate obtained in S2 is 1:1.5;
further, S3 specifically includes the following steps: adding alkali into tetrahydrofuran at room temperature, cooling to-10 ℃, dropwise adding triethyl phosphonoacetate, stirring for 10-30 min, dropwise adding 1- (4-methoxybenzyl) piperidine-2, 3-dione into tetrahydrofuran, then raising the temperature to room temperature for reaction until the raw materials are reacted, finally quenching with water, and purifying the obtained reaction liquid after quenching reaction to obtain (Z) -2- (1- (4-methoxybenzyl) -2-oxo piperidine-3-subunit) ethyl acetate; preferably, cooling to 0 ℃;
still more preferably, in S3, the base is sodium hydride (i.e., naH);
still more preferably, in S3, the tetrahydrofuran is anhydrous tetrahydrofuran;
still more preferably, in S3, the molar ratio of the 1- (4-methoxybenzyl) piperidine-2, 3-dione, triethylphosphonoacetate and sodium hydride is 0.8-1.5:1-2:1-2; preferably, the molar ratio of the 1- (4-methoxybenzyl) piperidine-2, 3-dione, triethylphosphonoacetate and sodium hydride is 1.0:1.5:1.5;
still more preferably, in S3, the purification refers to extracting the reaction solution with Dichloromethane (DCM) and saturated saline solution three times, mixing the organic phases, drying, and separating and purifying by column chromatography under the condition that the volume ratio of petroleum ether to ethyl acetate is 1:1, to obtain the target product;
further, in S4, the mol ratio of the (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate to the ammonium cerium nitrate is 1:1-2; further preferred, the molar ratio of (Z) -ethyl 2- (1- (4-methoxybenzyl) -2-oxopiperidin-3-ylidene) acetate to ceric ammonium nitrate is 1:1.3;
further, S4 specifically includes the following steps: dissolving (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate in a mixed solvent, adding ceric ammonium nitrate, adding salt water for quenching after the reaction is finished, and purifying the reaction solution to obtain (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate;
in S4, the mixed solvent is mixed solution of tertiary butanol and water, and the volume ratio of the mixed solvent to the mixed solution is 3-6:1; still more preferably, the mixed solvent is a mixed solution of tertiary butanol and water, and the volume ratio of the mixed solvent to the water is 4:1;
in S4, extracting the reaction solution with ethyl acetate and saturated saline for three times, mixing the organic phases, drying, separating and purifying by column chromatography under the condition that the volume ratio of petroleum ether to ethyl acetate is 0:100 to obtain the target product;
further, in S5, the molar ratio of the (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate to the diisobutyl aluminum hydride is 1.0:2-3; further preferred, in S5, the molar ratio of (Z) -ethyl 2- (2-oxopiperidin-3-ylidene) acetate to diisobutylaluminum hydride is 1.0:2.2;
further, S5 specifically includes the following steps: dissolving the product (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate of S4 in an organic solvent, cooling to-80 to-70 ℃ under the condition of nitrogen, dissolving diisobutyl aluminum hydride in the organic solvent, dripping into a reaction solution to react for a period of time, then heating to room temperature, sequentially adding water, sodium hydroxide and water, dripping each time for 10-20 seconds, and purifying the obtained reaction solution after the dripping is finished to obtain the product;
further, in S5, the organic solvent is selected from any one of anhydrous Dichloromethane (DCM) and anhydrous Tetrahydrofuran (THF);
further, in S5, the concentration of the sodium hydroxide is 0.5-2 mol/L; still more preferably, in S5, the sodium hydroxide concentration is 1mol/L;
in S5, extracting with Dichloromethane (DCM) for 1-3 times, mixing the extracted organic phases, drying, and separating and purifying by HPLC, wherein the mobile phase is methanol/water volume ratio of 20:80 to obtain the target product.
Advantageous effects
(1) The invention adopts piperidine as a substrate, and reacts with p-methoxybenzyl chloride under the condition of N, N-diisopropylethylamine to protect secondary amine, so that the subsequent side reaction of sodium hydride and hydrogen on the secondary amine is avoided, then the secondary amine is oxidized under the condition of iodine simple substance and iodobenzene diacetic acid, and then the secondary amine is reacted with triethyl phosphonoacetate to obtain alpha, beta unsaturated ester, then the protection of p-methoxybenzyl is removed mildly and efficiently by ceric ammonium nitrate, finally the ester is reduced to alcohol by diisobutyl aluminum hydride, finally piperidone alkaloid or analogues thereof are obtained through five steps of reactions.
(2) The invention adopts the optimal process conditions, so that the optimal yield and the shortest reaction time of each step of reaction are obtained.
Drawings
FIG. 1 is a specific flow chart of a synthetic reaction scheme for piperidones
FIG. 2 is a diagram showing a specific synthetic reaction scheme for piperidone compounds in example 1
FIG. 3 is a mass spectrum of piperidone compound in example 1
FIG. 4 shows the piperidone compound of example 1 1 H-NMR spectra
FIG. 5 is a piperidone compound of example 1 13 C-NMR spectra
FIG. 6 is an ultraviolet spectrum of piperidone compound as in example 1
FIG. 7 is an infrared spectrum of a piperidone compound of example 1
Detailed description of the preferred embodiments
The invention will be described in further detail with reference to examples and figures, but the method of implementation of the invention is not limited thereto.
The reagents used in the examples are commercially available as usual unless otherwise specified.
Example 1:
protection of S1 secondary amine: in a 100mL round bottom flask, 5.1g of piperidine and 3.88g of N, N-diisopropylethylamine were dissolved in 80mL of methylene chloride, 3.13g of p-methoxybenzyl chloride was added dropwise under ice bath conditions, and then the reaction was allowed to react overnight at room temperature, after the completion of the reaction, the reaction solution was washed with saturated brine, the aqueous layer was extracted twice with methylene chloride, and the organic phases were combined and dried, and then separated by column chromatography to give 1- (4-methoxybenzyl) piperidine whose nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum data were as shown below, which indicated that this step successfully synthesized 1- (4-methoxybenzyl) piperidine, the reaction yield: 90.9%;
nuclear magnetic data of 1- (4-methoxybenzyl) piperidine: 1 H NMR(300M,CDCl 3 ):δ7.22(d,J＝8.6Hz,2H),6.84(d,J＝8.6Hz,2H),3.80(s,3H),3.41(s,2H),2.35(s,4H),1.56(m,4H),1.47-1.30(m,2H). 13 C NMR(75MHz,CDCl 3 ):δ158.5,130.5,130.4,113.4,63.2,55.2,54.3,26.0,24.4。
oxidation of S2 piperidone derivatives: in a 250mL round bottom flask, 0.25g of the product obtained in S1, 0.77g of iodobenzene diacetic acid and 0.61g of elemental iodine were dissolved in 80mL of Tetrahydrofuran (THF), reacted at room temperature for 6 hours, then 0.39g of iodobenzene diacetic acid was added, reacted for 12 hours again, then the reaction was quenched with 48mL of saturated sodium thiosulfate, the reaction solution was extracted three times with ethyl acetate, the organic phases were combined and dried, and then separated by column chromatography to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione. The nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum data are shown as follows, which shows that the step successfully synthesizes 1- (4-methoxybenzyl) piperidine-2, 3-dione, and the reaction yield of the step is: 45.6%;
nuclear magnetic data of 1- (4-methoxybenzyl) piperidine-2, 3-dione: 1 H NMR(300M,CDCl 3 ):δ7.15(d,J＝8.7Hz,2H),6.78(d,J＝8.7Hz,2H),4.53(s,2H),3.71(s,3H),3.38(t,J＝6.0Hz,2H),2.63(t,J＝6.9Hz,2H),2.08-2.00(m,2H)； 13 C NMR(75MHz,CDCl 3 ):δ191.7,159.2,157.7,129.7,127.6,114.0,55.1,50.3,46.4,38.4,21.5。
connection of S3C-C bond: in a 50mL round bottom flask, 0.128g of sodium hydride (NaH, 3.2 mmol) was dissolved in dry 10mL of Tetrahydrofuran (THF), cooled to 0℃and then 0.51g of triethylphosphonoacetate was added dropwise, after 15 minutes, 0.33g of 1- (4-methoxybenzyl) piperidine-2, 3-dione, which was obtained as a product, was dissolved in 2mL of anhydrous Tetrahydrofuran (THF) and added dropwise to the reaction solution, followed by warming to room temperature, followed by Thin Layer Chromatography (TLC) followed by three extractions with Dichloromethane (DCM) and water after completion of the reaction, the organic phases were combined and dried, followed by column chromatography to give ethyl (Z) -2- (1- (4-methoxybenzyl) -2-oxopiperidin-3-ylidene) acetate. The nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum data are shown below, which shows that the step successfully synthesizes (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate; the reaction yield of the step: 76.0%;
nuclear magnetic data of ethyl (Z) -2- (1- (4-methoxybenzyl) -2-oxopiperidin-3-ylidene) acetate: 1 H NMR(300MHz,CDCl 3 ):δ7.06(d,J＝8.7Hz,2H),6.69(d,J＝8.7Hz,2H),5.85(s,1H),4.41(s,2H),4.16(q,J＝7.2Hz,2H),3.63(s,3H),3.10(t,J＝6.0Hz,2H),3.39(t,J＝6.0Hz,2H),1.75-1.67(m,2H),1.20(t,J＝7.1,3H)； 13 C NMR(75MHz,CDCl 3 ):δ167.6,161.8,158.6,135.2,129.2,128.4,128.5,113.5,60.4,54.8,49.2,46.5,29.7,22.2,13.7。
s4 removal of methoxybenzyl: in a 50mL round bottom flask, 0.22g of the (Z) -2- (1- (4-methoxybenzyl) -2-oxopiperidin-3-ylidene) acetic acid ethyl ester obtained as a product was dissolved in 10mL of a mixture of tert-butanol and water (volume ratio: 4:1), then 0.33g of ceric ammonium nitrate was added, 10wt% sodium chloride solution and ethyl acetate were added after 1 hour of reaction for extraction, the aqueous layer was washed three times with ethyl acetate, the organic phases were combined and dried, and then separated by column chromatography to obtain (Z) -2- (2-oxopiperidin-3-ylidene) acetic acid ethyl ester. The nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum data are shown below, which shows that the step successfully synthesizes the (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate; the reaction yield of the step: 43.0%;
nuclear magnetic data of ethyl (Z) -2- (2-oxopiperidin-3-ylidene) acetate: 1 H NMR(300M,CDCl 3 ):δ6.86(s,1H),5.97(s,1H),4.23(q,J＝7.2Hz,2H),3.35-3.30(m,2H),2.56-2.52(m,2H),1.92-1.83(m,2H),1.29(t,J＝7.1Hz,3H)； 13 C NMR(75MHz,CDCl 3 ):δ168.0,164.1,134.7,127.4,60.9,42.1,29.8,22.6,13.9。
reduction of S5 ester group: adding 0.0754g of the product obtained in S4 into a 100mL round bottom flask with a branch port, pumping out the air in a reaction bottle, filling nitrogen for protection, adding 3mL of anhydrous Dichloromethane (DCM), dissolving 1mL of diisobutyl aluminum hydride in 1mL of anhydrous Dichloromethane (DCM), cooling the reaction to-78 ℃, reacting, heating to room temperature after the reaction is finished, sequentially adding water, 1M sodium hydroxide and water, dropwise adding each time for 17 seconds, finally pouring the mixture into a separating funnel, extracting the water layer with Dichloromethane (DCM) for three times, merging organic phases, drying, and separating by column chromatography to obtain the final target product piperidone alkaloid. The nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum data are shown as follows, which shows that the final target product piperidone alkaloid is successfully synthesized in the step, and the reaction yield of the step is: 78.0%;
piperidone alkaloid nuclear magnetic data: 1 H NMR(300M,CDCl 3 ):δ6.19(m,1H),5.98(brs,1H),4.33(d,J＝6.1Hz,2H),3.38(m,2H),2.53(m,2H),1.88(m,2H)； 13 C NMR(75MHz,CDCl 3 ):δ167.1,141.6,130.8,59.4,42.7,31.9,22.9。
example 2: activity data of piperidone alkaloid
Dysidone is a new piperidone alkaloid separated from sponge Dysida sp.secondary metabolite collected in Zhanjiang city, and the compound acts on mouse mononuclear macrophage leukemia cells RAW264.7 at a concentration of 100 mu M, and the inhibition of Dysidone A on NO is observed by taking an inducible nitric oxide synthase inhibitor SMT as a positive control. The results show that the compound has a certain degree of NO inhibition activity and IC 50 The value was 378.27. Mu.M. However, since the amount of separation and extraction from the natural world is very small, synthetic methods are used insteadThe prospect of extraction and separation is quite considerable and feasible.
The foregoing examples are illustrative of the present invention and are not intended to be limiting, but are intended to be exemplary of the invention in any way without departing from the spirit and principles of the invention.
Claims (13)
1. The synthesis method of the active piperidone alkaloid is characterized in that the active piperidone alkaloid is DysidoneA, and the structure of the active piperidone alkaloid is shown as a formula (I):
the preparation method comprises the following steps:
protection of S1 secondary amine: piperidine is taken as a substrate, and reacts with p-methoxybenzyl chloride in the presence of N, N-diisopropylethylamine to obtain 1- (4-methoxybenzyl) piperidine;
oxidation of S2 piperidone derivatives: reacting the product 1- (4-methoxybenzyl) piperidine obtained in the step S1 with iodine simple substance and iodobenzene diacetic acid to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione;
connection of S3C-C bond: reacting the product 1- (4-methoxybenzyl) piperidine-2, 3-dione obtained in S2 with triethylphosphonoacetate to obtain (Z) -2- (1- (4-methoxybenzyl) -2-oxopiperidin-3-ylidene) acetic acid ethyl ester;
s4 removal of methoxybenzyl: reacting the (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate obtained in the step S3 with ceric ammonium nitrate, and removing the protection treatment of the p-methoxybenzyl group to obtain (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate;
reduction of S5 ester group: the ethyl (Z) -2- (2-oxo-piperidine-3-subunit) acetate obtained in S4 is reacted with diisobutyl aluminum hydride to obtain the final product (Z) -3- (2-hydroxyethylidene) piperidin-2-one.
2. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein in S1, the molar ratio of the p-methoxybenzyl chloride to the piperidine to the N, N-diisopropylethylamine is 0.5-2:0.5-2:1-1.8; further, in S1, the molar ratio of the p-methoxybenzyl chloride, the piperidine and the N, N-diisopropylethylamine is 1.1:1.0:1.5.
3. The method for synthesizing the active piperidone alkaloid as described in claim 1, wherein the specific step of S1 comprises the following steps: dissolving piperidine and N, N-diisopropylethylamine in dichloromethane, dropwise adding p-methoxybenzyl chloride under ice bath condition, reacting at room temperature overnight, and purifying the obtained reaction liquid after the reaction is finished to obtain the 1- (4-methoxybenzyl) piperidine.
4. The method for synthesizing active piperidone alkaloid as described in claim 3, wherein in S1, the purification is that the obtained reaction liquid is washed by saturated saline solution, the aqueous layer is extracted three times by dichloromethane, the organic phases are combined and dried, and then the separation and purification are carried out by column chromatography, wherein the elution condition is petroleum ether: the volume ratio of the ethyl acetate is 15:1, and the target product is obtained.
5. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein in S2, the molar ratio of the 1- (4-methoxybenzyl) piperidine to the iodobenzene diacetic acid to the iodine is as follows: 0.5-2:2.0-6.0:1.0-3.0; preferably, in S2, the molar ratio of 1- (4-methoxybenzyl) piperidine, iodobenzene diacetic acid and iodine is: 1.0:4.0:2.0.
6. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein the specific step of S2 comprises the steps of dissolving the product 1- (4-methoxybenzyl) piperidine in S1, iodobenzene diacetic acid and iodine in dry tetrahydrofuran, wherein the molar ratio of the 1- (4-methoxybenzyl) piperidine to the iodobenzene diacetic acid to the iodine is as follows: 0.5-2:1.0-3.0:1.0-3.0, stirring for 30-60 min, adding iodobenzene diacetic acid with the same molar weight as 1- (4-methoxybenzyl) piperidine, continuing to quench for 10-15 h by using saturated sodium thiosulfate solution, and purifying the obtained reaction solution after quenching reaction to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione; preferably, the molar ratio of the 1- (4-methoxybenzyl) piperidine to the iodobenzene diacetic acid to the iodine is as follows: 1.0:2.0:2.0; preferably, the stirring time is 50min; preferably, stirring is continued for a period of 12 hours.
7. The method for synthesizing the active piperidone alkaloid as described in claim 6, wherein in S2, the purification is performed by adding ethyl acetate and saturated saline water for three times, combining organic phases, drying, and separating and purifying by column chromatography, wherein the elution condition is petroleum ether: the volume ratio of the ethyl acetate is 5:1, and the target product is obtained.
8. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein in S3, the reaction molar ratio of 1- (4-methoxybenzyl) piperidine-2, 3-dione to triethyl phosphonoacetate is 0.8-1.5:1-2; preferably, the molar ratio of 1- (4-methoxybenzyl) piperidine-2, 3-dione to triethylphosphonoacetate is 1:1.5.
9. The method for synthesizing the active piperidone alkaloid as described in claim 8, wherein S3 comprises the following steps: adding alkali into tetrahydrofuran at room temperature, cooling to-10 ℃, dropwise adding triethyl phosphonoacetate, stirring for 10-30 min, dropwise adding 1- (4-methoxybenzyl) piperidine-2, 3-dione into tetrahydrofuran, then raising the temperature to room temperature for reaction until the raw materials are reacted, finally quenching with water, and purifying the obtained reaction liquid after quenching reaction to obtain (Z) -2- (1- (4-methoxybenzyl) -2-oxo piperidine-3-subunit) ethyl acetate; preferably, the base is sodium hydride (i.e., naH); preferably, the tetrahydrofuran is anhydrous tetrahydrofuran; preferably, the purification refers to the extraction of the reaction solution with Dichloromethane (DCM) and saturated brine three times, the combination of organic phases and drying, and then column chromatography, the elution conditions being petroleum ether: the volume ratio of the ethyl acetate is 1:1, and the target product is obtained after separation and purification; preferably, it is cooled to 0 ℃.
10. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein in S4, the molar ratio of (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate to ceric ammonium nitrate is 1:1-2; further preferred, the molar ratio of (Z) -ethyl 2- (1- (4-methoxybenzyl) -2-oxopiperidin-3-ylidene) acetate to ceric ammonium nitrate is 1:1.3.
11. The method for synthesizing the active piperidone alkaloid as described in claim 10, wherein S4 specifically comprises the following steps: dissolving (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate in a mixed solvent, adding ceric ammonium nitrate, adding saturated salt water for quenching after the reaction is finished, and purifying the reaction solution to obtain (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate; preferably, the mixed solvent is mixed solution of tertiary butanol and water, and the volume ratio of the mixed solvent to the mixed solution is 3-6:1; still more preferably, the mixed solvent is a mixed solution of tertiary butanol and water, and the volume ratio of the mixed solvent to the water is 4:1; further, in S4, the purification means that the reaction solution is extracted three times with ethyl acetate and saturated saline, the organic phases are combined and dried, and then the mixture is separated and purified by column chromatography, wherein the elution condition is petroleum ether: the volume ratio of the ethyl acetate is 0:100, and the target product is obtained.
12. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein in S5, the molar ratio of the (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate to the diisobutyl aluminum hydride is 1.0:2-3; preferably, in S5, the molar ratio of the (Z) -ethyl 2- (2-oxopiperidin-3-ylidene) acetate to diisobutylaluminum hydride is 1.0:2.2.
13. The method for synthesizing the active piperidone alkaloid as described in claim 12, wherein S5 specifically comprises the following steps: dissolving the product (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate of S4 in an organic solvent, cooling to-80 to-70 ℃ under the condition of nitrogen, dissolving diisobutyl aluminum hydride in the organic solvent, dripping into a reaction solution to react for a period of time, then heating to room temperature, sequentially adding water, sodium hydroxide and water, dripping each time for 10-20 seconds, and purifying the obtained reaction solution after the dripping is finished to obtain the product;
further, in S5, the organic solvent is selected from any one of anhydrous Dichloromethane (DCM) and anhydrous Tetrahydrofuran (THF);
further, in S5, the concentration of the sodium hydroxide is 0.5-2 mol/L; still more preferably, in S5, the sodium hydroxide concentration is 1mol/L;
in S5, extracting with Dichloromethane (DCM) for 1-3 times, mixing the extracted organic phases, drying, and separating and purifying by HPLC, wherein the mobile phase is methanol/water volume ratio of 20:80 to obtain the target product.
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