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CN-117304093-B - Piperidone alkaloid and analogues, synthesis method and application thereof

CN117304093BCN 117304093 BCN117304093 BCN 117304093BCN-117304093-B

Abstract

The invention provides a synthesis method of active piperidone alkaloid, wherein the active piperidone alkaloid is Dysidone A, raw material piperidine is adopted as a substrate, the active piperidone alkaloid reacts with p-methoxybenzyl chloride under the condition of N, N-diisopropylethylamine to protect secondary amine, subsequent side reaction of sodium hydride and hydrogen on the secondary amine is avoided, the secondary amine is oxidized under the condition of iodine simple substance and iodobenzene diacetic acid, the secondary amine is reacted with triethyl phosphonoacetate to obtain alpha, beta unsaturated ester, the protection of p-methoxybenzyl is removed with ammonium ceric nitrate in a mild and efficient manner, the ester is reduced to alcohol with diisobutyl aluminum hydride, and the piperidone alkaloid or the analogue thereof is obtained through five-step reaction.

Inventors

  • XU SHIHAI
  • ZHAO BINGXIN
  • FENG PENGJU
  • LEI YU
  • Li baiao

Assignees

  • 暨南大学

Dates

Publication Date
20260508
Application Date
20230926

Claims (20)

  1. 1. The synthesis method of the active piperidone alkaloid is characterized in that the active piperidone alkaloid is Dysidone A, and the structure of the active piperidone alkaloid is shown as a formula (I): (I) The preparation method comprises the following steps: S1 secondary amine protection, namely, taking piperidine as a substrate, and reacting with p-methoxybenzyl chloride in the presence of N, N-diisopropylethylamine to obtain 1- (4-methoxybenzyl) piperidine; oxidizing the S2 piperidone derivative, namely reacting the product 1- (4-methoxybenzyl) piperidine obtained in the S1 with iodine simple substance and iodobenzene diacetic acid to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione; connection of S3C-C bond, namely, reacting the product 1- (4-methoxybenzyl) piperidine-2, 3-dione obtained in S2 with triethyl phosphonoacetate to obtain (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate; S4, removing the methoxybenzyl group, namely reacting the (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate obtained in the S3 with ceric ammonium nitrate, and removing the protection treatment of the methoxybenzyl group to obtain (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate; Reduction of the S5 ester group the ethyl (Z) -2- (2-oxopiperidin-3-ylidene) acetate obtained in S4 is reacted with diisobutylaluminum hydride to give the final product (Z) -3- (2-hydroxyethylidene) piperidin-2-one.
  2. 2. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein in S1, the molar ratio of p-methoxybenzyl chloride, piperidine and N, N-diisopropylethylamine is 0.5-2:0.5-2:1-1.8.
  3. 3. The method for synthesizing the active piperidone alkaloid according to claim 2, wherein in S1, the molar ratio of the p-methoxybenzyl chloride to the piperidine to the N, N-diisopropylethylamine is 1.1:1.0:1.5.
  4. 4. The method for synthesizing the active piperidone alkaloid according to claim 2 or 3, wherein the specific step S1 comprises the following steps of dissolving piperidine and N, N-diisopropylethylamine in dichloromethane, dropwise adding p-methoxybenzyl chloride under the 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.
  5. 5. The method for synthesizing the active piperidone alkaloid as described in claim 4, wherein in S1, the purification is that the obtained reaction liquid is washed by saturated saline solution, the water layer is extracted by dichloromethane three times, the organic phases are combined and dried, and then the target product is obtained by column chromatography separation and purification, wherein the elution condition is that the volume ratio of petroleum ether to ethyl acetate is 15:1.
  6. 6. 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 0.5-2:2.0-6.0:1.0-3.0.
  7. 7. The method for synthesizing the active piperidone alkaloid according to claim 6, wherein in S2, the molar ratio of 1- (4-methoxybenzyl) piperidine to iodobenzene diacetic acid to iodine is 1.0:4.0:2.0.
  8. 8. The method for synthesizing the active piperidone alkaloid according to claim 6 or 7, wherein the specific step of S2 is characterized in that the product 1- (4-methoxybenzyl) piperidine, iodobenzene diacetic acid and iodine in S1 are dissolved in dry tetrahydrofuran, the molar ratio of the 1- (4-methoxybenzyl) piperidine to the iodobenzene diacetic acid to the iodine is 0.5-2:1.0-3.0:1.0-3.0, the iodobenzene diacetic acid with the same molar amount as the 1- (4-methoxybenzyl) piperidine is added after stirring for 30-60 min, the mixture is further stirred for 10-15 h and then quenched by saturated sodium thiosulfate solution, and the obtained reaction solution is purified after the quenching reaction, so that the 1- (4-methoxybenzyl) piperidine-2, 3-dione is obtained.
  9. 9. The method for synthesizing the active piperidone alkaloid as described in claim 8, wherein in S2, the molar ratio of 1- (4-methoxybenzyl) piperidine to iodobenzene diacetic acid to iodine is 1.0:2.0:2.0.
  10. 10. The method for synthesizing active piperidone alkaloid as in claim 8, wherein in S2, the stirring time is 50 min.
  11. 11. The method for synthesizing the active piperidone alkaloid as in claim 8, wherein in S2, the continuous stirring time is 12 hours.
  12. 12. The method for synthesizing the active piperidone alkaloid as in claim 8, 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 under the condition that the volume ratio of petroleum ether to ethyl acetate is 5:1, thus obtaining the target product.
  13. 13. 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 triethylphosphonoacetate is 0.8-1.5:1-2.
  14. 14. The method for synthesizing the active piperidone alkaloid according to claim 13, wherein in S3, the reaction molar ratio of the 1- (4-methoxybenzyl) piperidine-2, 3-dione to the triethyl phosphonoacetate is 1:1.5.
  15. 15. The method for synthesizing the active piperidone alkaloid according to claim 13 or 14, wherein S3 specifically comprises the steps of 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 by water, and purifying the obtained reaction liquid after quenching reaction to obtain (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate.
  16. 16. The method for synthesizing active piperidone alkaloid as in claim 15, wherein in S3, the base is sodium hydride (i.e., naH).
  17. 17. The method for synthesizing the active piperidone alkaloid as in claim 15, wherein in S3, the tetrahydrofuran is anhydrous tetrahydrofuran.
  18. 18. The method for synthesizing the active piperidone alkaloid as in claim 15, wherein in S3, the purification refers to extracting the reaction solution with Dichloromethane (DCM) and saturated saline water three times, combining the organic phases, drying, and then performing column chromatography under the condition that the volume ratio of petroleum ether to ethyl acetate is 1:1, and separating and purifying to obtain the target product.
  19. 19. The method for synthesizing active piperidone alkaloid as in claim 15, wherein in S3, it is cooled to 0 ℃.
  20. 20. The method for synthesizing the active piperidone alkaloid according to claim 1, wherein in S4, the molar ratio of (Z) -ethyl 2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) acetate to ceric ammonium nitrate is 1:1-2.

Description

Piperidone alkaloid and analogues, synthesis method and application thereof 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 organic intermediate of nitrogen heterocyclic ring, only small-scale production is carried out in China at present, 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, and the pyridine is also reported to be prepared by electrolytic reduction in foreign countries. 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, 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, such as the first analgesic drug of pethidine (pethidine) synthesized in 1939 and the therapeutic index widely used at present, which are high in safety, and a series of 3, 5-di (arylene) -4-piperidone and N-substituted-acryloyl derivatives thereof are synthesized by Jonathan and the like, and biological activity tests show that many compounds have cytotoxic activities on murine leukemia cells P388 and human leukemia cells L1210 and human Molt 4/C8 and CEM tumors, and the mechanism of action is to inhibit biosynthesis of tumor cell DNA, RNA and protein, and hopefully select high-efficiency anticancer drugs from the group. Disclosure of Invention The invention provides a synthesis method of an active piperidone alkaloid, which is DysidoneA and has a structure shown in a formula (I): The preparation method comprises the following steps: s1 secondary amine protection, namely, taking piperidine as a substrate, and reacting with p-methoxybenzyl chloride in the presence of N, N-diisopropylethylamine to obtain 1- (4-methoxybenzyl) piperidine; Oxidizing the S2 piperidone derivative, namely reacting the product 1- (4-methoxybenzyl) piperidine obtained in the S1 with iodine simple substance and iodobenzene diacetic acid to obtain 1- (4-methoxybenzyl) piperidine-2, 3-dione; connection of S3C-C bond, namely, reacting the product 1- (4-methoxybenzyl) piperidine-2, 3-dione obtained in S2 with triethyl phosphonoacetate to obtain (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate; S4, removing the methoxybenzyl group, namely reacting the (Z) -2- (1- (4-methoxybenzyl) -2-oxo-piperidine-3-subunit) ethyl acetate obtained in the S3 with ceric ammonium nitrate, and removing the protection treatment of the methoxybenzyl group to obtain (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate; Reduction of S5 ester group, namely, reacting the (Z) -2- (2-oxo-piperidine-3-subunit) ethyl acetate obtained in 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 to the piperidine to the N, N-diisopropylethylamine is 0.5-2:0.5-2:1-1.8, and further, in S1, the mol ratio of the p-methoxybenzyl chlor