WO2018099146A1 - Method for asymmetrically synthesizing aspidosperma alkaloid - Google Patents

Method for asymmetrically synthesizing aspidosperma alkaloid Download PDF

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WO2018099146A1
WO2018099146A1 PCT/CN2017/098979 CN2017098979W WO2018099146A1 WO 2018099146 A1 WO2018099146 A1 WO 2018099146A1 CN 2017098979 W CN2017098979 W CN 2017098979W WO 2018099146 A1 WO2018099146 A1 WO 2018099146A1
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formula
compound
organic solvent
reaction
molar ratio
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PCT/CN2017/098979
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French (fr)
Chinese (zh)
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姜雪峰
王能中
白磊阳
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华东师范大学
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Priority claimed from CN201611076812.XA external-priority patent/CN106674222B/en
Priority claimed from CN201710320158.0A external-priority patent/CN107312001B/en
Application filed by 华东师范大学 filed Critical 华东师范大学
Publication of WO2018099146A1 publication Critical patent/WO2018099146A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of application technology of organic compound synthesis, and particularly relates to a method for asymmetrically synthesizing alkaloids of the genus.
  • Indole alkaloids are a class of compounds that are widely found in nature. Vinblastine and Vincristine are widely used in anti-cancer drugs developed by Eli Lilly. vintafolide is a compound developed by Endocyte for the treatment of non-small cell carcinoma and is currently in clinical phase II. They belong to the biguanide vinca alkaloids. Another class of monoterpenoid alkaloids, the A. sylvestris alkaloids (Aspidosperma alkaloids), also have good biological activity. For example, Tabersonine is superior to cisplatin in inhibiting human cancer cell line SK-BR-3. Cisplatin), Jerantinine-E is more cytotoxic to human KB cells and so on.
  • the present invention provides a method for the asymmetric synthesis of A. serrata alkaloids (Aspidosperma alkaloids).
  • the method can be started from a large number of known intermediates, and provides a good foundation for the subsequent large-scale production and structure-activity relationship research of A. sylvestris.
  • the invention provides a method for asymmetrically synthesizing alkaloids of the genus Bacillus, by a compound of the formula (1a) and a compound of the formula (1b) by [4+2] cycloaddition, decarboxylation, reduction, Wittig reaction, oxidation, Fischer ⁇ The reaction of 6 steps, such as rearrangement, gives the key intermediate compound of formula (4), and the compound of formula (4) is further converted by a substitution reaction, a reduction reaction or the like to obtain a series of white alkaloids.
  • the prepared compound of the formula (4) is prepared by two methods:
  • R 1 is selected from an alkyl group; preferably, a C1-C20 alkyl group; further preferably, a C1-C10 alkyl group; further preferably, a methyl group, an ethyl group, an isopropyl group, a t-butyl group; Preferably, it is a methyl group.
  • R 2 is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, alkoxy, halogen; further preferably, hydrogen, C1-C20 alkyl, trifluoromethyl, C1-C20 alkoxy, halogen; further preferably Is hydrogen, C1-C10 alkyl, trifluoromethyl, C1-C10 alkoxy, halogen; further preferably, hydrogen, methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, iodo; Further preferred are hydrogen, 2-methyl, 2-trifluoromethyl, 2-methoxy, 3-methoxy, 4-methoxy, 2,3-dimethoxy, 3,4-di Methoxy, 2-fluoro, 2-chloro, 2-bromo, 2-iodo; further preferably, hydrogen, 2-methoxy, 3-methoxy, 2,3-dimethoxy.
  • the temperature of the addition reaction is from 90 ° C to 110 ° C; preferably, 90 ° C, 100 ° C, 110 ° C; more preferably, 110 ° C.
  • the addition reaction time is from 24 hours to 60 hours; preferably, 24 hours, 48 hours, 60 hours; further preferably, 60 hours.
  • the organic solvent is one or more selected from the group consisting of toluene, benzene, dichloromethane, and the like; preferably, toluene.
  • the molar ratio of the compound of the formula (1a) to the compound of the formula (1b) (or the compound of the formula (ent-1b)) is 1: (1 to 2); preferably, 1:1, 1:1.2 1, 1.5, 1: 2; further preferably, the optimum molar ratio is 1:1.5.
  • the temperature of the substitution reaction is 0 to 40 ° C; preferably, room temperature (25 ° C).
  • the time of the substitution reaction is from 3 hours to 10 hours; preferably, it is 5 hours.
  • the action of the trifluoroacetic acid is to remove Boc and t-Bu.
  • the molar ratio of the compound of the formula (1c) or the compound of the formula (ent-1c) to trifluoroacetic acid is 1: (5 to 15); preferably, 1:5, 1:10. 1,15; further preferably, the optimum molar ratio is 1:10.
  • the temperature of the substitution reaction is 0 to 40 ° C; preferably, room temperature (25 ° C).
  • the time of the substitution reaction is from 15 hours to 20 hours; preferably, 15 hours.
  • the mixed solvent is selected from the group consisting of a mixed solvent of tetrahydrofuran and water, a mixed solvent of acetone and water, and the like; preferably, a mixed solvent of tetrahydrofuran and water, wherein an optimum volume ratio of tetrahydrofuran to water It is 2:1.
  • the brown oily liquid the molar ratio of the benzyl chloroformate to the sodium hydrogencarbonate is 1:5: (5 to 20); preferably, 1:5:5, 1:5: 10, 1:5:15, 1:5:20; further preferably, the optimum molar ratio is 1:5:20.
  • the temperature of the elimination reaction is from 25 ° C to 40 ° C; preferably, 25 ° C, 40 ° C; further preferably, room temperature (25 ° C).
  • the elimination reaction time is 0.5 to 2 hours; preferably, 0.5 hours, 1 hour, 1.5 hours, 2 hours; further preferably 2 hours.
  • the organic solvent is one or more selected from the group consisting of dichloromethane, 1,2-dichloroethane, and the like; preferably, it is dichloromethane.
  • the elimination reaction is carried out under irradiation of an 8W to 200W incandescent lamp; preferably, 8W, 25W, 50W, 100W, 150W, 200W; further preferably, the elimination reaction is in the 200W incandescent The lamp is illuminated.
  • the temperature of the addition reaction is 0 to 40 ° C; preferably, 0 ° C, 25 ° C, 40 ° C; further preferably, room temperature (25 ° C).
  • the addition reaction is carried out for 10 minutes to 1 hour; preferably, 10 minutes, 30 minutes, 1 hour; more preferably, 30 minutes.
  • the organic solvent is one or more selected from the group consisting of dichloromethane, 1,2-dichloroethane, and the like; preferably, it is dichloromethane.
  • the compound of the formula (1d) (or the compound of the formula (ent-1d), the ratio of iodobenzene acetate, iodine and triethylsilylhydrogen is 1:2:(0.1 to 0.5):5; Ground, 1:2:0.1:5, 1:2:0.2:5, 1:2:0.3:5, 1:2:0.4:5, 1:2:0.5:5; further preferably, the best molar The ratio is 1:2:0.2:5.
  • the temperature of the reduction reaction is -60 ° C to - 40 ° C; preferably, it is -60 ° C, -50 ° C, -40 ° C; further preferably, it is -40 ° C.
  • the reduction reaction time is from 1 hour to 5 hours; preferably, it is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours; further preferably, 3 hours.
  • the organic solvent is selected from the group consisting of toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane; preferably, toluene.
  • the molar ratio of the compound of the formula (1) to diisobutylaluminum hydride in the reduction reaction is 1: (1.2 to 2); preferably, 1:1.2, 1:1.5, 1:2; further preferably, it is 1:1.5.
  • the diisobutylaluminum hydride is added at -78 °C.
  • the temperature of the substitution reaction is from 25 ° C to 110 ° C; preferably, 25 ° C, 110 ° C; more preferably, 110 ° C.
  • the time of the substitution reaction is from 1 hour to 4 hours; preferably, it is 1 hour, 2 hours, 4 Hour; further preferably, 4 hours.
  • the organic solvent is selected from the group consisting of toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane; preferably, toluene.
  • the step of synthesizing the compound of formula (2) comprises dissolving the compound of formula (1) in toluene, adding diisobutylaluminum hydride, and raising the reaction to -40 ° C for 3 hours to obtain a colorless oil. liquid.
  • the compound of the formula (2) is obtained.
  • the diisobutylaluminum hydride is added at -78 ° C; the diisobutylaluminum hydride is added by means of an auto-injection pump at -78 ° C for 30 minutes.
  • the temperature of the oxidation reaction is from 0 ° C to 25 ° C; preferably, 0 ° C, 25 ° C; preferably, room temperature (25 ° C).
  • the oxidation reaction time is 30 minutes to 2 hours; preferably, 30 minutes, 1 hour, 2 hours; further preferably, 1 hour.
  • the organic solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane; preferably, dichloromethane.
  • the molar ratio of the compound of the formula (2) to the Dess-Martin periodinator is 1: (1.2 to 5); preferably, 1:1.2, 1:1.5, 1:2. , 1:3, 1:4, 1:5; further preferably, 1:1.2.
  • the Dess-Martin periodinane is (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzeneiodo-3 ( 1H)-ketone, its structural formula is
  • the temperature of the substitution reaction is from 25 ° C to 110 ° C; preferably, 25 ° C, 50 ° C, 80 ° C, 110 ° C; more preferably, 110 ° C.
  • the substitution reaction time is from 12 hours to 48 hours; preferably, 12 hours, 24 hours, 36 hours, 48 hours; further preferably, 24 hours.
  • the first organic solvent is selected from the group consisting of ethanol, benzene, toluene, xylene, 1,2-dichloroethane; preferably, toluene.
  • the molar ratio of the compound of the formula (3) to the aromatic hydrazine is 1: (2 to 4); preferably, 1: 2, 1:3, 1:4; Further preferably, it is 1:4.
  • the temperature of the rearrangement reaction is 40 ° C to 120 ° C; preferably 40 ° C, 50 ° C, 60 ° C, 70 ° C, 80 ° C, 90 ° C, 100 ° C, 110 ° C, 120 ° C; further preferably, 80 ° C.
  • the rearrangement reaction time is from 1 hour to 5 hours; preferably, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours; further preferably, 1 hour.
  • the organic solvent is selected from the group consisting of 1,2-dichloroethane, acetic acid, ethanol, tert-butanol, and 1,4-dioxane; preferably 1,2-Dichloroethane.
  • the molar ratio of the aromatic hydrazine to the trifluoroacetic acid in the rearrangement reaction is 1: (10 to 50); preferably, 1:10, 1:20, 1:30, 1 : 40, 1:50; further preferably, 1:20.
  • the temperature of the substitution reaction is from 80 ° C to 100 ° C; preferably, 80 ° C, 90 ° C, 100 ° C; more preferably, 80 ° C.
  • the substitution reaction is carried out for 12 to 36 hours; preferably, 12 hours, 24 hours, 36 hours; further preferably 12 hours.
  • the organic solvent is selected from the group consisting of methanol, methanol/tetrahydrofuran, ethanol/tetrahydrofuran, methanol/N,N-dimethylformamide, and N,N-dimethylformamide; Preferably, it is methanol/tetrahydrofuran (1:1 by volume), ethanol/tetrahydrofuran (volume ratio 1:3), methanol/N,N-dimethylformamide (volume ratio 1:3); further preferably, Methanol / N, N-dimethylformamide (1:3 by volume).
  • the molar ratio of the compound of the formula (4), triethylamine and tetrakistriphenylphosphine palladium is 1:3:(0.05 to 0.2); preferably, 1:3: 0.05, 1:3:0.1, 1:3:0.2; further preferably, 1:3:0.1.
  • the substitution reaction is preferably carried out under a carbon monoxide atmosphere.
  • the temperature of the reduction reaction is from 0 ° C to 50 ° C; preferably, 0 ° C, 25 ° C, 50 ° C; preferably, 25 ° C.
  • the reduction reaction time is 5 hours to 10 hours; preferably, 5 hours, 8 hours, 10 hours; further preferably, 8 hours.
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, ethanol, and tetrahydrofuran; preferably, methanol.
  • the molar ratio of the compound of the formula (5), triethylamine and palladium/carbon is 1:5: (0.1 to 0.5); preferably, 1:5:0.1, 1 : 5: 0.2, 1: 5: 0.5; further preferably, 1: 5: 0.2.
  • the temperature of the substitution reaction is from 80 ° C to 100 ° C; preferably, 80 ° C, 90 ° C, 100 ° C; more preferably, 80 ° C.
  • the substitution reaction time is 30 minutes to 2 hours; preferably, 30 minutes, 1 hour, 2 hours; further preferably, 30 minutes.
  • the organic solvent is selected from the group consisting of benzene, toluene, xylene, and tetrahydrofuran; preferably, toluene.
  • the molar ratio of the compound of the formula (6) to the Lawesson's reagent is 1: (1 to 1.2); preferably, 1:1, 1:1.1, 1:1.2; further preferably Ground, 1:1.1.
  • the Lawesson's reagent is bis(4-methoxyphenyl)-1,3-dithio- 2,4-diphosphane-2,4-disulfide. , its structural formula is
  • the temperature of the reduction reaction is from 40 ° C to 110 ° C; preferably, 40 ° C, 100 ° C, 110 ° C; preferably, 110 ° C.
  • the reduction reaction is carried out for 10 minutes to 2 hours; preferably, 10 minutes, 30 minutes, 1 hour, 2 hours; further preferably, 10 minutes.
  • the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,2-dichloroethane, and benzene; preferably, toluene.
  • the molar ratio of the compound of the formula (7), diisopropylethylamine and p-toluene flavonolamine is 1:5: (1 to 2.5); preferably, It is 1:5:1, 1:5:2, 1:5:2.5; further preferably, it is 1:5:2.5.
  • the temperature of the substitution reaction is from -10 ° C to 25 ° C; preferably, it is -10 ° C, 0 ° C, 25 ° C; further preferably, it is 0 ° C.
  • the substitution reaction time is from 1 hour to 5 hours; preferably, it is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours; further preferably, 2 hours.
  • the organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, and 1,2-dichloroethane; preferably, dichloromethane.
  • the molar ratio of the compound of the formula (8) to the cerium salt of trimethoxytetrafluoroborate is 1: (1 to 3); preferably, 1:1, 1: 2, 1:3; further preferably, 1:3.
  • the temperature of the reduction reaction is from 0 ° C to 25 ° C; preferably, 0 ° C, 25 ° C; further preferably, 25 ° C.
  • the reduction reaction time is 30 minutes to 2 hours; preferably, 30 minutes, 1 hour, 2 hours; further preferably, 1 hour.
  • the organic solvent is selected from the group consisting of methanol, dichloromethane, tetrahydrofuran, 1,2-dichloroethane; preferably, methanol.
  • the molar ratio of the compound of the formula (8) to sodium borohydride is 1: (5 to 20); Ground selection is 1:5, 1:10, 1:20; further preferably, 1:10.
  • the temperature of the reduction reaction is from 0 ° C to 50 ° C; preferably, 0 ° C, 25 ° C, 50 ° C; further preferably, 25 ° C.
  • the reduction reaction time is 5 hours to 10 hours; preferably, 5 hours, 8 hours, 10 hours; further preferably, 8 hours.
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, ethanol, and tetrahydrofuran; preferably, methanol.
  • the molar ratio of the compound of the formula (4), triethylamine and palladium/carbon is 1:5: (0.2 to 0.5); preferably, 1:5:0.2, 1 : 5: 0.5; further preferably, 1:5: 0.2.
  • the temperature of the reduction reaction is from 25 ° C to 70 ° C; preferably, 25 ° C, 50 ° C, 70 ° C; more preferably, 70 ° C.
  • the reduction reaction time is 5 hours to 15 hours; preferably, 5 hours, 10 hours, 13 hours, 15 hours; further preferably, 13 hours.
  • the organic solvent is selected from the group consisting of tetrahydrofuran, toluene, and dichloromethane; preferably, tetrahydrofuran.
  • the molar ratio of the compound of the formula (9) to lithium tetrahydrogenate is 1: (5 to 10); preferably, 1:5, 1:10; further preferably, 1:10.
  • the temperature of the reduction reaction is from 0 ° C to 50 ° C; preferably, 0 ° C, 25 ° C, 50 ° C; further preferably, 25 ° C.
  • the reduction reaction time is from 1 hour to 3 hours; preferably, it is 1 hour, 2 hours, 3 hours; further preferably, 3 hours.
  • the organic solvent is selected from the group consisting of pyridine, triethylamine, 2,6-lutidine; preferably, pyridine.
  • the molar ratio of the compound of the formula (10), pyridine and acetic anhydride is 1: (5-10): 5; preferably, 1:5:5, 1:10: 5; Further preferably, the optimum molar ratio is 1:10:5.
  • the base is one or more selected from the group consisting of pyridine, sodium acetate, triethylamine and the like; preferably, it is a pyridine.
  • the acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride and the like; preferably, acetic anhydride.
  • the specific steps of the asymmetric synthesis of a compound of formula (1) (or a compound of formula (ent-1)) of the present invention include:
  • Step (a) A compound of the formula (1a) and a compound of the formula (1b) (or a compound of the formula (ent-1b)) are dissolved in toluene, and refluxed at 110 ° C for 60 hours. The toluene was removed under reduced pressure and directly subjected to column chromatography to give a white solid (1c) compound (or compound (ent-1c)).
  • Step (b) A compound of the formula (1c) (or a compound of the formula (ent-1c)) is dissolved in trifluoroacetic acid.
  • the reaction was carried out for 5 hours at room temperature.
  • the trifluoroacetic acid was removed under reduced pressure to give a brown oily liquid.
  • the oily liquid was dissolved in a solvent mixture of tetrahydrofuran and water, and then sodium hydrogencarbonate solid and benzyl chloroacetate were sequentially added and reacted at room temperature for 15 hours.
  • the reaction solution was adjusted to pH 2-3 with 4N HCl and THF was evaporated under reduced pressure.
  • the aqueous phase was extracted 5 times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated.
  • Step (c) A compound of the formula (1d) (or a compound of the formula (ent-1d)) is dissolved in dichloromethane, and then iodobenzene acetate and iodine are sequentially added, and the mixture is irradiated at room temperature for 2 hours under irradiation with a 200 W incandescent lamp. The incandescent lamp was then removed, triethylsilyl hydrogen was added and reacted at room temperature for 30 minutes. The toluene is removed under reduced pressure, and the residue is directly subjected to column chromatography to give a compound (1) or a compound of formula (1).
  • reaction route of the compound of the formula (1) of the present invention is shown by the route (1');
  • the specific steps of the asymmetric synthesis of the Alkaloids of the present invention include:
  • Step (b) The compound of the formula (2) was dissolved in dichloromethane, and Dess-Martin periodinane was added at 0 ° C, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the saturated sodium thiosulfate solution and the saturated sodium hydrogencarbonate solution were successively added, the system was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step (c) dissolving the compound of formula (3) in toluene, sequentially adding 4A molecular sieve, sodium carbonate and ArNHNH 2 , wherein ArNHNH 2 may be benzoquinone, 2-methoxyphenylhydrazine, 3-methoxyphenylhydrazine or 2,3-dimethoxybenzoquinone.
  • ArNHNH 2 may be benzoquinone, 2-methoxyphenylhydrazine, 3-methoxyphenylhydrazine or 2,3-dimethoxybenzoquinone.
  • the reaction was refluxed to 110 ° C for 12 hours, then the same amount of sodium carbonate and ArNHNH 2 was added, toluene was removed under reduced pressure , and then dissolved in 1,2-dichloroethane, trifluoroacetic acid was added, and the reaction was refluxed to 80 ° C for 1 hour.
  • a saturated sodium hydrogencarbonate solution was added, the mixture was extracted with dichloromethane, dried over an
  • Step (d) The compound of the formula (4) is dissolved in methanol/N,N-dimethylformamide (1:3), and triethylamine and tetrakistriphenylphosphine palladium are added at 25 ° C, and the reaction is raised to 80 ° C. Stir for 12 hours. The reaction was quenched with aq. EtOAc (EtOAc)EtOAc.
  • Step (e) The compound of the formula (5) is dissolved in methanol, and triethylamine and Pd/C are sequentially added.
  • the reaction flask was replaced with hydrogen and stirred under a hydrogen atmosphere (hydrogen balloon) for 8 hours, filtered, and the filter cake was washed with ethyl acetate.
  • the solvent was removed under reduced pressure and purified by column chromatography to yield white compound (6).
  • Step (f) The compound of the formula (6) is dissolved in toluene, and Lawesson's reagent is added at 25 ° C, and the reaction is raised to 80 ° C for 30 minutes. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was diluted with a saturated sodium chloride solution, and the mixture was evaporated. The compound of formula (7) is obtained as a pale yellow solid.
  • Step (g) The compound of the formula (7) is dissolved in toluene, N,N-diisopropylethylamine is added at room temperature, and the newly prepared p-tolueneoxyl chloride is added under a nitrogen atmosphere, and the reaction is refluxed to 110 ° C. 10 minutes. The solvent was removed under reduced pressure and purified by column chromatography to yield a pale yellow solid compound (8).
  • Step (h) The compound of the formula (8) is dissolved in dichloromethane, and trimethoxytetrafluoroborate is added at 0 °C. The reaction was carried out at 0 ° C for 2 hours, methanol was added to the reaction system, and after stirring for 15 minutes, sodium borohydride was added. The reaction was carried out at 0 ° C for 30 minutes. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc.
  • Step (i) The compound of the formula (4) is dissolved in methanol, and triethylamine and Pd/C are sequentially added at room temperature.
  • the reaction flask was replaced with hydrogen and stirred under a hydrogen atmosphere (hydrogen balloon) for 8 hours, filtered, and the filter cake was washed with ethyl acetate. The solvent was removed under reduced pressure to give a white solid.
  • Step (j) Dissolve the white solid in tetrahydrofuran, add lithium tetrahydrogenate at 0 ° C, and reflux to 70 ° C for 12 hours. The reaction is cooled to 0 ° C. The reaction is sequentially quenched with water, 15% aqueous sodium hydroxide and water. The mixture was filtered, and the filtrate was washed with ethyl acetate. The solvent was evaporated under reduced pressure and purified to afford white oil (-)-Aspidospermidine.
  • Step (k) Dissolve (-)-Aspidospermidine in pyridine and add acetic anhydride at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was quenched with aqueous EtOAc. Column chromatography gave the colorless liquid (+)-N-Acetylaspidospermidine.
  • the present invention also provides a class of alkaloid compounds having the structure of formula (1c), formula (1d), formula (1), formula (ent-1c), formula (ent-1d), and formula (ent-1). Show:
  • the present invention also proposes a series of A. sylvestris alkaloid compounds having the structure of formula (2), formula (3), formula (4), formula (5), formula (6), formula (7), formula ( 8), formula (9):
  • R 1 is selected from alkyl; preferably, C1-C20 alkyl; more preferably, C1-C10 alkyl; more preferably, methyl, ethyl, isopropyl, tert-butyl group; further Preferably, it is a methyl group.
  • R 2 is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, alkoxy, halogen; further preferably, hydrogen, C1-C20 alkyl, trifluoromethyl, C1-C20 alkoxy, halogen; further preferably Is hydrogen, C1-C10 alkyl, trifluoromethyl, C1-C10 alkoxy, halogen; further preferably, hydrogen, methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, iodo; Further preferred is hydrogen or methoxy.
  • the present invention also provides the alkaloids of the formula (10) to (12), the formula (1c), the formula (1d), the formula (1), the formula (ent-1c), and the formula ( The use of the alkaloid compound represented by ent-1d), formula (ent-1) or formula (2) to formula (9) for the preparation of albino alkaloids.
  • the invention has the beneficial effects of the present invention, which provides an efficient and convenient method for asymmetrically synthesizing the alkaloids of the genus Bacillus, and synthesizes some white saponins from a large number of compounds of the formula (1a) and the compound of the formula (1b).
  • the compound of formula (1c) (10.40 g, 22.02 mmol, 1.0 equiv.) was dissolved in trifluoroacetic acid (20 mL). The reaction was carried out for 5 hours at room temperature. The trifluoroacetic acid was removed under reduced pressure to give a brown oily liquid (purified without column chromatography);
  • This oily liquid was dissolved in a mixed solvent of tetrahydrofuran (140 mL) and water (70 mL), and then sodium hydrogencarbonate solid (37.34 g, 440.33 mmol, 20.0 equiv.) and benzyl chloroformate (18.77 g, 110.08 mmol, 5.0 Equiv.), react at room temperature for 15 hours.
  • the reaction solution was adjusted to pH 2-3 with 4N HCl and THF was evaporated under reduced pressure.
  • the aqueous phase was extracted 5 times with ethyl acetate.
  • the compound of the formula (1) (6.48 g, 14.43 mmol, 1.0 equiv.) was dissolved in freshly distilled dichloromethane (140 mL), followed by the addition of iodobenzene (9.30 g, 28.86 mmol, 2.0 equiv.) and iodine (0.73) g, 2.89 mmol, 0.2 equiv.), 200 W incandescent lamp was irradiated at room temperature for 2 hours. The incandescent lamp was then removed and triethylsilicohydrogen (8.37 g, 72.15 mmol, 5.0 equiv.) was added and allowed to react at room temperature for 30 minutes. After the toluene was removed under reduced pressure, the title compound (5.38 g, 92% yield) was obtained as a colorless oil.
  • the compound of the formula (1) (4.09 g, 2.61 mmol, 1.0 equiv.) was dissolved in toluene (100 mL), and diisobutylaluminum hydride (10 mL, 3.91 mmol) was added at -78 °C through an auto-injection pump over 30 minutes. 1.5 equiv., 1.5 M in toluene) The reaction was stirred at -40 ° C for 3 hours. The reaction was quenched with saturated sodium potassium tartrate solution (20 mL) and stirred at room temperature until the reaction mixture was clarified. The toluene was removed under reduced pressure, the aqueous layer was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated
  • the compound of the formula (2a) (3.55 g, 7.65 mmol, 1.0 equiv.) was dissolved in dichloromethane (76 mL), and then, at 0 ° C, Dess-Martin oxidant (3.89 g, 9.17 mmol, 1.2 equiv.) was added. Stir to room temperature and stir for 1 hour. After completion of the reaction, a saturated sodium thiosulfate solution (25 mL) and a saturated sodium hydrogen carbonate solution (25 mL) were successively added, and the mixture was dried over anhydrous sodium sulfate (dichloromethane) (3 ⁇ 50 mL), filtered, and the solvent was removed under reduced pressure. The title compound (3.23 g, 92%) was obtained.
  • the compound of the formula (4a) (2.79 g, 4.93 mmol, 1.0 equiv.) was dissolved in methanol/N,N-dimethylformamide (1/3, 48 mL), and triethylamine (1.50 g, 14.8) Methyl, 3.0 equiv.) and Pd(PPh 3 ) 4 (570 mg, 0.493 mmol, 0.1 equiv.).
  • the reaction system was replaced with carbon monoxide and the reaction was allowed to rise to 80 ° C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, and a saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL). After filtration, the solvent was removed under reduced pressure and then purified tolululululululululululululililililililililili g).
  • the compound of the formula (6a) (873 mg, 2.28 mmol, 1.0 equiv.) was dissolved in toluene (23 mL). Lawesson's reagent (1.02 g, 2.51 mmol, 1.1 equiv.) was added at room temperature. The reaction was refluxed to 80 ° C for 30 minutes. . After the reaction was completed, it was cooled to room temperature, and a saturated sodium chloride solution (50 mL) was added to the reaction system. The system was extracted with ethyl acetate (3 ⁇ 50 mL). The organic phase was washed with saturated aqueous sodium chloride (3 ⁇ 50 mL), dried over anhydrous sodium sulfate. 609 mg, 67%).
  • the compound of the formula (7a) (589 mg, 1.48 mmol, 1.0 equiv.) was dissolved in toluene (60 mL), and N,N-diisopropylethylamine (955 mg, 7.39 mmol, 5.0 equiv.) was added at room temperature.
  • the newly prepared p-tolueneoxyl chloride (645 mg, 3.69 mmol, 2.5 equiv.) was added.
  • the reaction was allowed to reflux to 110 ° C for 10 minutes. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated, evaporated, mjjjjjjj
  • the compound of the formula (4b) (35.4 mg, 0.066 mmol, 1.0 equiv.) was dissolved in methanol (6.6 mL), followed by triethylamine (33.4 mg, 0.33 mmol, 5.00 equiv.) and Pd/C (10 wt%, 14 mg, 0.0132 mmol, 0.20 equiv.).
  • the reaction flask was replaced with hydrogen and stirred under a hydrogen atmosphere (hydrogen balloon) for 8 hours, filtered, and ethyl acetate (3 ⁇ 50 mL) washed. The solvent was removed under reduced pressure to give a white solid (purified by column chromatography).
  • the white solid obtained above was dissolved in tetrahydrofuran (1 mL), and a mixture of three portions of lithium aluminum hydride (25 mg, 0.66 mmol, 10.0 equiv.) was added in three portions at -78 ° C, and the mixture was refluxed at 70 ° C for 13 hours. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was stirred with water (250 ⁇ L), 15% sodium hydroxide solution (250 ⁇ L) and water (750 ⁇ L) for 30 minutes, and then filtered to remove solid contents.
  • lithium aluminum hydride 25 mg, 0.66 mmol, 10.0 equiv.

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Abstract

Disclosed is a method for asymmetrically synthesizing aspidosperma alkaloid. In this method, a key intermediate of formula (4) is obtained by 6 steps of reactions, including [4+2] cycloaddition of the compound of formula (1a) and the compound of formula (1b), decarboxylation, reduction, Wittig reaction, oxidation and Fischer indole rearrangement, and further transformed through several steps to obtain a series of aspidosperma alkaloids. The reaction scheme is shown in scheme (1). The method can start from abundant and readily available compounds of formulas (1a) and (1b), and provides good technical support for subsequent realization of large-scale production of the aspidosperma alkaloid and study of structure-activity relationship.

Description

一种不对称合成白坚木属生物碱的方法Method for asymmetric synthesis of Alkaloids 技术领域Technical field
本发明属于有机化合物合成工艺应用技术领域，具体涉及一种不对称合成白坚木属生物碱的方法。The invention belongs to the technical field of application technology of organic compound synthesis, and particularly relates to a method for asymmetrically synthesizing alkaloids of the genus.
背景技术Background technique
吲哚生物碱是一类广泛存在于自然界的化合物。Vinblastine和Vincristine是Eli Lilly公司开发的广泛用于抗癌的药物，vintafolide是Endocyte公司开发的用于治疗非小细胞癌的一种化合物，目前处于临床II期。它们属于双吲哚vinca类生物碱。另外一类单萜吲哚类生物碱—白坚木属生物碱(Aspidosperma类生物碱)也有很好的生物活性，例如Tabersonine对人体癌细胞系SK-BR-3的抑制作用优于顺铂(Cisplatin)，Jerantinine-E对人体KB细胞有更强的细胞毒性等等。但是他们在自然界中丰度低，提取较困难，这增加了对其生理学和药理学活性方面的研究难度，阻碍了对该类化合物的进一步研究和应用。过去的多数路线只能合成单一的非手性天然产物，并不能实现结构多样性的手性合成。因此发明一种不对称合成白坚木属生物碱的方法非常重要。Indole alkaloids are a class of compounds that are widely found in nature. Vinblastine and Vincristine are widely used in anti-cancer drugs developed by Eli Lilly. vintafolide is a compound developed by Endocyte for the treatment of non-small cell carcinoma and is currently in clinical phase II. They belong to the biguanide vinca alkaloids. Another class of monoterpenoid alkaloids, the A. sylvestris alkaloids (Aspidosperma alkaloids), also have good biological activity. For example, Tabersonine is superior to cisplatin in inhibiting human cancer cell line SK-BR-3. Cisplatin), Jerantinine-E is more cytotoxic to human KB cells and so on. However, they are low in nature and difficult to extract, which increases the difficulty of studying their physiological and pharmacological activities and hinders further research and application of such compounds. Most of the past routes can only synthesize a single achiral natural product, and cannot achieve chiral synthesis of structural diversity. Therefore, it is very important to invent a method for asymmetrically synthesizing Alkaloids.
Figure PCTCN2017098979-appb-000001
Figure PCTCN2017098979-appb-000001
发明内容Summary of the invention
本发明提供了一种不对称合成白坚木属生物碱(Aspidosperma类生物碱)的方法。所述方法能够从大量可得的已知中间体出发，为后续实现白坚木属生物碱的规模化生产及构效关系研究提供良好的基础。The present invention provides a method for the asymmetric synthesis of A. serrata alkaloids (Aspidosperma alkaloids). The method can be started from a large number of known intermediates, and provides a good foundation for the subsequent large-scale production and structure-activity relationship research of A. sylvestris.
本发明提供的不对称合成白坚木属生物碱的方法，以式(1a)化合物和式(1b)化合物经[4+2]环加成，脱羧，还原，Wittig反应，氧化，Fischer吲哚重排等6个步骤的反应得到关键中间体式(4)化合物，式(4)化合物再分别经过取代反应、还原反应等转化得到一系列白坚木属生物碱。The invention provides a method for asymmetrically synthesizing alkaloids of the genus Bacillus, by a compound of the formula (1a) and a compound of the formula (1b) by [4+2] cycloaddition, decarboxylation, reduction, Wittig reaction, oxidation, Fischer吲哚The reaction of 6 steps, such as rearrangement, gives the key intermediate compound of formula (4), and the compound of formula (4) is further converted by a substitution reaction, a reduction reaction or the like to obtain a series of white alkaloids.
具体包括以下步骤：Specifically, the following steps are included:
(一)式(1)化合物的合成(a) Synthesis of the compound of formula (1)
步骤(l)：将式(1a)化合物和式(1b)化合物(或式(ent-1b)化合物)溶于有机溶剂中，进行加成反应，得到式(1c)化合物(或式(ent-1c)化合物)。Step (l): dissolving the compound of the formula (1a) and the compound of the formula (1b) (or the compound of the formula (ent-1b)) in an organic solvent to carry out an addition reaction to obtain a compound of the formula (1c) (or formula (ent- 1c) compound).
步骤(m)式(1d)化合物或式(ent-1d)化合物的合成Step (m) Synthesis of a compound of formula (1d) or a compound of formula (ent-1d)
(m-1)将式(1c)化合物或式(ent-1c)化合物溶于三氟乙酸中，进行取代反应，得到褐色油状液体5-溴-7-乙基-8-氧代-2,3,3a,4,7,7a-六氢-1H-4,7-(环氧甲烷基)吲哚-2-羧酸；(m-1) A compound of the formula (1c) or a compound of the formula (ent-1c) is dissolved in trifluoroacetic acid to carry out a substitution reaction to obtain a 5-bromo-7-ethyl-8-oxo-2 liquid as a brown oil. 3,3a,4,7,7a-hexahydro-1H-4,7-(epoxymethylalkyl)indole-2-carboxylic acid;
(m-2)将褐色油状液体5-溴-7-乙基-8-氧代-2,3,3a,4,7,7a-六氢-1H-4,7-(环氧甲烷基)吲哚-2-羧酸溶于混合溶剂中，加入碳酸氢钠固体和氯甲酸苄酯，进行取代反应，得到式(1d)化合物或式(ent-1d)化合物。(m-2) a brown oily liquid 5-bromo-7-ethyl-8-oxo-2,3,3a,4,7,7a-hexahydro-1H-4,7-(epoxymethylalkyl) The hydrazine-2-carboxylic acid is dissolved in a mixed solvent, and a sodium hydrogencarbonate solid and benzyl chloroformate are added to carry out a substitution reaction to obtain a compound of the formula (1d) or a compound of the formula (ent-1d).
步骤(n)式(1)化合物或式(ent-1)化合物的合成Step (n) Synthesis of a compound of formula (1) or a compound of formula (ent-1)
(n-1)将式(1d)化合物(或式(ent-1d)化合物)、醋酸碘苯和碘溶于有机溶剂中，进行消去反应，得到亚胺阳离子中间体化合物；(n-1) dissolving a compound of the formula (1d) (or a compound of the formula (ent-1d), iodobenzene acetate and iodine in an organic solvent to carry out an elimination reaction to obtain an imine cation intermediate compound;
(n-2)将亚胺阳离子中间体化合物和三乙基硅氢进行加成反应，得到式(1)化合物(或式(ent-1)化合物)。(n-2) An addition reaction of an imide cationic intermediate compound and triethylsilylhydrogen to obtain a compound of the formula (1) (or a compound of the formula (ent-1)).
反应过程如路线(1)所示：The reaction process is shown in route (1):
Figure PCTCN2017098979-appb-000002
Figure PCTCN2017098979-appb-000002
Figure PCTCN2017098979-appb-000003
Figure PCTCN2017098979-appb-000003
(二)白坚木属生物碱的合成(2) Synthesis of alkaloids from the genus Baijianmu
步骤(a)式(2)化合物的合成Synthesis of compound of formula (a) formula (2)
(a-1)将式(1)化合物将溶于有机溶剂中，加入二异丁基氢化铝，进行还原反应，得到无色油状液体(3aS，4S，7S，7aR)-5-溴-7-乙基-4-羟基-7-((E)-3-甲氧基-3-氧代丙-1-烯基)-2,3，3a，4，7，7a-六氢-1H-吲哚-1-羧酸苄酯。(a-1) The compound of the formula (1) is dissolved in an organic solvent, and diisobutylaluminum hydride is added to carry out a reduction reaction to obtain a colorless oily liquid (3aS, 4S, 7S, 7aR)-5-bromo-7. -ethyl-4-hydroxy-7-((E)-3-methoxy-3-oxoprop-1-enyl)-2,3,3a,4,7,7a-hexahydro-1H- Benzyl-1-carboxylate.
(a-2)将步骤(a-1)得到的无色油状液体(3aS，4S，7S，7aR)-5-溴-7-乙基-4-羟基-7-((E)-3-甲氧基-3-氧代丙-1-烯基)-2,3，3a，4，7，7a-六氢-1H-吲哚-1-羧酸苄酯溶于有机溶剂中，加入Wittig试剂Ph3P＝CHCO2R1，进行取代反应，得到式(2)化合物。(a-2) Colorless oily liquid (3aS, 4S, 7S, 7aR)-5-bromo-7-ethyl-4-hydroxy-7-((E)-3- obtained in the step (a-1) Benzyl-3-oxoprop-1-enyl)-2,3,3a,4,7,7a-hexahydro-1H-indole-1-carboxylic acid benzyl ester is dissolved in an organic solvent and added to Wittig The reagent Ph 3 P=CHCO 2 R 1 is subjected to a substitution reaction to obtain a compound of the formula (2).
步骤(b)：将式(2)化合物溶于有机溶剂中，加入戴斯-马丁氧化剂，进行氧化反应，得到式(3)化合物。Step (b): Dissolving the compound of the formula (2) in an organic solvent, adding a Dess-Martin oxidizing agent, and performing an oxidation reaction to obtain a compound of the formula (3).
步骤(c)式(4)化合物的合成Step (c) Synthesis of the compound of formula (4)
(c-1)将式(3)化合物和芳香肼溶于有机溶剂中，进行取代反应，得到芳腙中间体；(c-1) dissolving the compound of the formula (3) and the aromatic hydrazine in an organic solvent to carry out a substitution reaction to obtain an aryl hydrazine intermediate;
(c-2)将芳腙中间体溶于有机溶剂中，加入三氟乙酸，进行重排反应，得到式(4)化合物。(c-2) The aryl hydrazine intermediate is dissolved in an organic solvent, and trifluoroacetic acid is added to carry out a rearrangement reaction to obtain a compound of the formula (4).
制备的式(4)化合物通过两种方法制备目标化合物：The prepared compound of the formula (4) is prepared by two methods:
方法一：method one:
步骤(d)：将式(4)化合物溶于有机溶剂中，加入三乙胺和四三苯基膦钯，进行取代反应，得到得到式(5)化合物。Step (d): The compound of the formula (4) is dissolved in an organic solvent, and a substitution reaction is carried out by adding triethylamine and tetrakistriphenylphosphine palladium to obtain a compound of the formula (5).
步骤(e)：将式(5)化合物溶于有机溶剂中，依次加入三乙胺和钯/碳(Pd/C)，进行还原反应，得到式(6)化合物。Step (e): The compound of the formula (5) is dissolved in an organic solvent, and triethylamine and palladium/carbon (Pd/C) are sequentially added to carry out a reduction reaction to obtain a compound of the formula (6).
步骤(f)：将式(6)化合物溶于有机溶剂中，加入Lawesson’s试剂，进行取代反应，得到式(7)化合物。Step (f): The compound of the formula (6) is dissolved in an organic solvent, and Lawesson's reagent is added to carry out a substitution reaction to obtain a compound of the formula (7).
步骤(g)：将式(7)化合物溶于有机溶剂中，加入对甲基苯亚黄酰氯胺和二异丙基乙胺，进行还原反应，得到式(8)化合物。Step (g): The compound of the formula (7) is dissolved in an organic solvent, and p-methylbenzene-xylyl chloramine and diisopropylethylamine are added to carry out a reduction reaction to obtain a compound of the formula (8).
步骤(h)：式(12)化合物的合成Step (h): Synthesis of a compound of formula (12)
(h-1)将式(8)化合物溶于有机溶剂中，加入三甲氧基四氟硼酸鎓盐，进行取代反应，得到硫甲基化合物中间体；(h-1) dissolving the compound of the formula (8) in an organic solvent, adding a ruthenium trimethoxytetrafluoroborate salt, and performing a substitution reaction to obtain a thiomethyl compound intermediate;
(h-2)然后加入硼氢化钠，进行还原反应，得到目标化合物式(12)化合物白坚木属生物碱。(h-2) Then, sodium borohydride is added to carry out a reduction reaction to obtain a compound of the formula (12), a compound of the formula A.
方法二： Method Two:
步骤(i)：将式(4)化合物溶于有机溶剂中，加入三乙胺和钯/碳(Pd/C)，进行还原反应，得到式(9)化合物。Step (i): The compound of the formula (4) is dissolved in an organic solvent, and triethylamine and palladium/carbon (Pd/C) are added to carry out a reduction reaction to obtain a compound of the formula (9).
步骤(j)：将式(9)化合物溶于有机溶剂中，依次加入四氢铝锂，进行还原反应，得到式(10)化合物白坚木属生物碱。Step (j): Dissolving the compound of the formula (9) in an organic solvent, and sequentially adding lithium tetrahydrogenate to carry out a reduction reaction to obtain a compound of the formula (10).
步骤(k)：在有机溶剂中，将式(10)化合物加入碱和乙酰化试剂，进行取代反应，分别得到目标化合物式(11)化合物白坚木属生物碱。Step (k): a compound of the formula (10) is added to a base and an acetylating reagent in an organic solvent to carry out a substitution reaction to obtain a compound of the formula (11), a compound of the formula A.
反应过程如路线(2)所示；The reaction process is as shown in route (2);
Figure PCTCN2017098979-appb-000004
Figure PCTCN2017098979-appb-000004
其中，所述芳香肼的结构式为
Figure PCTCN2017098979-appb-000005
Wherein the structural formula of the aromatic oxime is
Figure PCTCN2017098979-appb-000005
其中，所述芳腙中间体的结构式为：
Figure PCTCN2017098979-appb-000006
Wherein, the structural formula of the aryl hydrazine intermediate is:
Figure PCTCN2017098979-appb-000006
其中，R1选自烷基；优选地，为C1-C20烷基；进一步优选地，为C1-C10烷基；进一步优选地，为甲基、乙基、异丙基、叔丁基；进一步优选地，为甲基。Wherein R 1 is selected from an alkyl group; preferably, a C1-C20 alkyl group; further preferably, a C1-C10 alkyl group; further preferably, a methyl group, an ethyl group, an isopropyl group, a t-butyl group; Preferably, it is a methyl group.
R2选自氢、烷基、三氟甲基、烷氧基、卤素；进一步优选地，为氢、C1-C20烷基、三氟甲基、C1-C20烷氧基、卤素；进一步优选地，为氢、C1-C10烷基、三氟甲基、C1-C10烷氧基、卤素；进一步优选地，氢、甲基、三氟甲基、甲氧基、氟、氯、溴、碘；进一步优选地为氢、2-甲基、2-三氟甲基、2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、3,4-二甲氧基、2-氟、2-氯、2-溴、2-碘；进一步优选地，为氢、2-甲氧基、3-甲氧基、2,3-二甲氧基。R 2 is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, alkoxy, halogen; further preferably, hydrogen, C1-C20 alkyl, trifluoromethyl, C1-C20 alkoxy, halogen; further preferably Is hydrogen, C1-C10 alkyl, trifluoromethyl, C1-C10 alkoxy, halogen; further preferably, hydrogen, methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, iodo; Further preferred are hydrogen, 2-methyl, 2-trifluoromethyl, 2-methoxy, 3-methoxy, 4-methoxy, 2,3-dimethoxy, 3,4-di Methoxy, 2-fluoro, 2-chloro, 2-bromo, 2-iodo; further preferably, hydrogen, 2-methoxy, 3-methoxy, 2,3-dimethoxy.
步骤(l)中，所述加成反应的温度为90℃～110℃；优选地，为90℃、100℃、110℃；进一步优选地为，110℃。In the step (1), the temperature of the addition reaction is from 90 ° C to 110 ° C; preferably, 90 ° C, 100 ° C, 110 ° C; more preferably, 110 ° C.
步骤(l)中，所述加成反应的时间为24小时～60小时；优选地，为24小时、48小时、60小时；进一步优选地，为60小时。In the step (1), the addition reaction time is from 24 hours to 60 hours; preferably, 24 hours, 48 hours, 60 hours; further preferably, 60 hours.
步骤(l)中，所述有机溶剂选自甲苯、苯、二氯甲烷等中的一种或多种；优选地，为甲苯。In the step (1), the organic solvent is one or more selected from the group consisting of toluene, benzene, dichloromethane, and the like; preferably, toluene.
步骤(l)中，式(1a)化合物和式(1b)化合物(或式(ent-1b)化合物)的摩尔比为1:(1～2)；优选地，为1:1、1:1.2、1:1.5、1:2；进一步优选地，最佳摩尔比为1:1.5。In the step (1), the molar ratio of the compound of the formula (1a) to the compound of the formula (1b) (or the compound of the formula (ent-1b)) is 1: (1 to 2); preferably, 1:1, 1:1.2 1, 1.5, 1: 2; further preferably, the optimum molar ratio is 1:1.5.
步骤(m-1)中，所述取代反应的温度为0～40℃；优选地，为室温(25℃)。In the step (m-1), the temperature of the substitution reaction is 0 to 40 ° C; preferably, room temperature (25 ° C).
步骤(m-1)中，所述取代反应的时间为3小时～10小时；优选地，为5小时。In the step (m-1), the time of the substitution reaction is from 3 hours to 10 hours; preferably, it is 5 hours.
步骤(m-1)中，所述三氟乙酸的作用是脱除Boc和t‐Bu。In the step (m-1), the action of the trifluoroacetic acid is to remove Boc and t-Bu.
步骤(m-1)中，所述式(1c)化合物或式(ent-1c)化合物和三氟乙酸的摩尔比为1:(5～15)；优选地，为1:5、1:10、1:15；进一步优选地，最佳摩尔比为1:10。In the step (m-1), the molar ratio of the compound of the formula (1c) or the compound of the formula (ent-1c) to trifluoroacetic acid is 1: (5 to 15); preferably, 1:5, 1:10. 1,15; further preferably, the optimum molar ratio is 1:10.
步骤(m-2)中，所述取代反应的温度为0～40℃；优选地，为室温(25℃)。In the step (m-2), the temperature of the substitution reaction is 0 to 40 ° C; preferably, room temperature (25 ° C).
步骤(m-2)中，所述取代反应的时间为15小时～20小时；优选地，为15小时。In the step (m-2), the time of the substitution reaction is from 15 hours to 20 hours; preferably, 15 hours.
步骤(m-2)中，所述混合溶剂选自四氢呋喃和水的混合溶剂、丙酮和水的混合溶剂等；优选地，为四氢呋喃和水的混合溶剂，其中，四氢呋喃和水的最佳体积比为2:1。 In the step (m-2), the mixed solvent is selected from the group consisting of a mixed solvent of tetrahydrofuran and water, a mixed solvent of acetone and water, and the like; preferably, a mixed solvent of tetrahydrofuran and water, wherein an optimum volume ratio of tetrahydrofuran to water It is 2:1.
步骤(m-2)中，所述褐色油状液体，氯甲酸苄酯和碳酸氢钠的摩尔比为1:5:(5～20)；优选地，为1:5:5、1:5:10、1:5:15、1:5:20；进一步优选地，最佳摩尔比为1:5:20。In the step (m-2), the brown oily liquid, the molar ratio of the benzyl chloroformate to the sodium hydrogencarbonate is 1:5: (5 to 20); preferably, 1:5:5, 1:5: 10, 1:5:15, 1:5:20; further preferably, the optimum molar ratio is 1:5:20.
步骤(n-1)中，所述消去反应的温度为25℃～40℃；优选地，为25℃、40℃；进一步优选地，为室温(25℃)。In the step (n-1), the temperature of the elimination reaction is from 25 ° C to 40 ° C; preferably, 25 ° C, 40 ° C; further preferably, room temperature (25 ° C).
步骤(n-1)中，所述消去反应的时间为0.5～2小时；优选地，为0.5小时、1小时、1.5小时、2小时；进一步优选地为，2小时。In the step (n-1), the elimination reaction time is 0.5 to 2 hours; preferably, 0.5 hours, 1 hour, 1.5 hours, 2 hours; further preferably 2 hours.
步骤(n-1)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷等中的一种或多种；优选地，为二氯甲烷。In the step (n-1), the organic solvent is one or more selected from the group consisting of dichloromethane, 1,2-dichloroethane, and the like; preferably, it is dichloromethane.
步骤(n-1)中，所述消去反应在8W～200W白炽灯的照射下进行；优选地，为8W、25W、50W、100W、150W、200W；进一步优选地，所述消去反应在200W白炽灯的照射下进行。In the step (n-1), the elimination reaction is carried out under irradiation of an 8W to 200W incandescent lamp; preferably, 8W, 25W, 50W, 100W, 150W, 200W; further preferably, the elimination reaction is in the 200W incandescent The lamp is illuminated.
步骤(n-2)中，所述加成反应的温度为0～40℃；优选地，为0℃、25℃、40℃；进一步优选地，为室温(25℃)。In the step (n-2), the temperature of the addition reaction is 0 to 40 ° C; preferably, 0 ° C, 25 ° C, 40 ° C; further preferably, room temperature (25 ° C).
步骤(n-2)中，所述加成反应的时间为10分钟～1小时；优选地，为10分钟、30分钟、1小时；进一步优选地为，30分钟。In the step (n-2), the addition reaction is carried out for 10 minutes to 1 hour; preferably, 10 minutes, 30 minutes, 1 hour; more preferably, 30 minutes.
步骤(n-2)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷等中的一种或多种；优选地，为二氯甲烷。In the step (n-2), the organic solvent is one or more selected from the group consisting of dichloromethane, 1,2-dichloroethane, and the like; preferably, it is dichloromethane.
步骤(n)中，式(1d)化合物(或式(ent-1d)化合物)，醋酸碘苯，碘和三乙基硅氢的摩尔比为1:2:(0.1～0.5):5；优选地，为1:2:0.1:5、1:2:0.2:5、1:2:0.3:5、1:2:0.4:5、1:2:0.5:5；进一步优选地，最佳摩尔比为1:2:0.2:5。In the step (n), the compound of the formula (1d) (or the compound of the formula (ent-1d), the ratio of iodobenzene acetate, iodine and triethylsilylhydrogen is 1:2:(0.1 to 0.5):5; Ground, 1:2:0.1:5, 1:2:0.2:5, 1:2:0.3:5, 1:2:0.4:5, 1:2:0.5:5; further preferably, the best molar The ratio is 1:2:0.2:5.
步骤(a-1)中，所述还原反应的温度为–60℃～–40℃；优选地，为–60℃、–50℃、–40℃；进一步优选地，为–40℃。In the step (a-1), the temperature of the reduction reaction is -60 ° C to - 40 ° C; preferably, it is -60 ° C, -50 ° C, -40 ° C; further preferably, it is -40 ° C.
步骤(a-1)中，所述还原反应的时间为1小时～5小时；优选地，为1小时、2小时、3小时、4小时、5小时；进一步优选地为，3小时。In the step (a-1), the reduction reaction time is from 1 hour to 5 hours; preferably, it is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours; further preferably, 3 hours.
步骤(a-1)中，所述还原反应中，有机溶剂选自甲苯、四氢呋喃、二氯甲烷、1,2-二氯乙烷；优选地为，甲苯。In the step (a-1), in the reduction reaction, the organic solvent is selected from the group consisting of toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane; preferably, toluene.
步骤(a-1)中，所述还原反应中，式(1)化合物与二异丁基氢化铝的摩尔比为1:(1.2～2)；优选地，为1:1.2、1:1.5、1:2；进一步优选地，为1:1.5。In the step (a-1), the molar ratio of the compound of the formula (1) to diisobutylaluminum hydride in the reduction reaction is 1: (1.2 to 2); preferably, 1:1.2, 1:1.5, 1:2; further preferably, it is 1:1.5.
步骤(a-1)中，优选地，所述二异丁基氢化铝在–78℃加入。In the step (a-1), preferably, the diisobutylaluminum hydride is added at -78 °C.
步骤(a-2)中，所述取代反应的温度为25℃～110℃；优选地，为25℃、110℃；进一步优选地为，110℃。In the step (a-2), the temperature of the substitution reaction is from 25 ° C to 110 ° C; preferably, 25 ° C, 110 ° C; more preferably, 110 ° C.
步骤(a-2)中，所述取代反应的时间为1小时～4小时；优选地，为1小时、2小时、4 小时；进一步优选地为，4小时。In the step (a-2), the time of the substitution reaction is from 1 hour to 4 hours; preferably, it is 1 hour, 2 hours, 4 Hour; further preferably, 4 hours.
步骤(a-2)中，所述取代反应中，有机溶剂选自甲苯、四氢呋喃、二氯甲烷、1,2-二氯乙烷；优选地为，甲苯。In the step (a-2), in the substitution reaction, the organic solvent is selected from the group consisting of toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane; preferably, toluene.
所述取代反应中，无色油状液体与Wittig试剂Ph3P＝CHCO2R1的摩尔比为1:(1.5～2)；优选地，为1:1.5、1:2；进一步优选地，为1:1.5。In the substitution reaction, the molar ratio of the colorless oily liquid to the Wittig reagent Ph 3 P=CHCO 2 R 1 is 1: (1.5 to 2); preferably, 1:1.5, 1:2; further preferably, 1:1.5.
在一具体实施方式中，式(2)化合物的合成步骤包括：将式(1)化合物溶于甲苯中，加入二异丁基氢化铝，反应升至–40℃搅拌3小时，得到无色油状液体。将此油状液体溶于甲苯中，加入Ph3P＝CHCO2R1，反应升至110℃回流4小时。得到式(2)化合物。其中，优选地，所述二异丁基氢化铝在–78℃加入；所述二异丁基氢化铝在–78℃通过自动进样泵历时30分钟加入。In a specific embodiment, the step of synthesizing the compound of formula (2) comprises dissolving the compound of formula (1) in toluene, adding diisobutylaluminum hydride, and raising the reaction to -40 ° C for 3 hours to obtain a colorless oil. liquid. This oily liquid was dissolved in toluene, Ph 3 P=CHCO 2 R 1 was added , and the reaction was refluxed to 110 ° C for 4 hours. The compound of the formula (2) is obtained. Of these, preferably, the diisobutylaluminum hydride is added at -78 ° C; the diisobutylaluminum hydride is added by means of an auto-injection pump at -78 ° C for 30 minutes.
步骤(b)中，所述氧化反应的温度为0℃～25℃；优选地，为0℃、25℃；优选地，为室温(25℃)。In the step (b), the temperature of the oxidation reaction is from 0 ° C to 25 ° C; preferably, 0 ° C, 25 ° C; preferably, room temperature (25 ° C).
步骤(b)中，所述氧化反应的时间为30分钟～2小时；优选地，为30分钟、1小时、2小时；进一步优选地为，1小时。In the step (b), the oxidation reaction time is 30 minutes to 2 hours; preferably, 30 minutes, 1 hour, 2 hours; further preferably, 1 hour.
步骤(b)中，所述氧化反应中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、四氢呋喃、1,4-二氧六环；优选地为，二氯甲烷。In the step (b), in the oxidation reaction, the organic solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane; preferably, dichloromethane.
步骤(b)中，所述氧化反应中，式(2)化合物和戴斯-马丁氧化剂的摩尔比为1:(1.2～5)；优选地，为1:1.2、1:1.5、1:2、1:3、1:4、1:5；进一步优选地，为1:1.2。In the step (b), in the oxidation reaction, the molar ratio of the compound of the formula (2) to the Dess-Martin periodinator is 1: (1.2 to 5); preferably, 1:1.2, 1:1.5, 1:2. , 1:3, 1:4, 1:5; further preferably, 1:1.2.
步骤(b)中，所述氧化反应中，所述戴斯-马丁氧化剂为(1,1,1-三乙酰氧基)-1,1-二氢-1,2-苯碘酰-3(1H)-酮，其结构式为
Figure PCTCN2017098979-appb-000007
In the step (b), in the oxidation reaction, the Dess-Martin periodinane is (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzeneiodo-3 ( 1H)-ketone, its structural formula is
Figure PCTCN2017098979-appb-000007
步骤(c-1)中，所述取代反应的温度为25℃～110℃；优选地，为25℃、50℃、80℃、110℃；进一步优选地为，110℃。In the step (c-1), the temperature of the substitution reaction is from 25 ° C to 110 ° C; preferably, 25 ° C, 50 ° C, 80 ° C, 110 ° C; more preferably, 110 ° C.
步骤(c-1)中，所述取代反应的时间为12小时～48小时；优选地为，12小时、24小时、36小时、48小时；进一步优选地为，24小时。In the step (c-1), the substitution reaction time is from 12 hours to 48 hours; preferably, 12 hours, 24 hours, 36 hours, 48 hours; further preferably, 24 hours.
步骤(c-1)中，所述取代反应中，所述第一有机溶剂选自乙醇、苯、甲苯、二甲苯、1,2-二氯乙烷；优选地为，甲苯。In the step (c-1), in the substitution reaction, the first organic solvent is selected from the group consisting of ethanol, benzene, toluene, xylene, 1,2-dichloroethane; preferably, toluene.
步骤(c-1)中，所述取代反应中，式(3)化合物与芳香肼的摩尔比为1:(2～4)；优选地，为1:2、1:3、1:4；进一步优选地，为1:4。 In the step (c-1), in the substitution reaction, the molar ratio of the compound of the formula (3) to the aromatic hydrazine is 1: (2 to 4); preferably, 1: 2, 1:3, 1:4; Further preferably, it is 1:4.
步骤(c-2)中，所述重排反应的温度为40℃～120℃；优选地为，40℃、50℃、60℃、70℃、80℃、90℃、100℃、110℃、120℃；进一步优选地为，80℃。In the step (c-2), the temperature of the rearrangement reaction is 40 ° C to 120 ° C; preferably 40 ° C, 50 ° C, 60 ° C, 70 ° C, 80 ° C, 90 ° C, 100 ° C, 110 ° C, 120 ° C; further preferably, 80 ° C.
步骤(c-2)中，所述重排反应的时间为1小时～5小时；优选地为，1小时、2小时、3小时、4小时、5小时；进一步优选地为，1小时。In the step (c-2), the rearrangement reaction time is from 1 hour to 5 hours; preferably, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours; further preferably, 1 hour.
步骤(c-2)中，所述重排反应中，所述有机溶剂选自1,2-二氯乙烷、乙酸、乙醇、叔丁醇、1,4-二氧六环；优选地为，1,2-二氯乙烷。In the step (c-2), in the rearrangement reaction, the organic solvent is selected from the group consisting of 1,2-dichloroethane, acetic acid, ethanol, tert-butanol, and 1,4-dioxane; preferably 1,2-Dichloroethane.
步骤(c-2)中，所述重排反应中，芳香腙与三氟乙酸的摩尔比为1:(10～50)；优选地，为1:10、1:20、1:30、1:40、1:50；进一步优选地，为1:20。In the step (c-2), the molar ratio of the aromatic hydrazine to the trifluoroacetic acid in the rearrangement reaction is 1: (10 to 50); preferably, 1:10, 1:20, 1:30, 1 : 40, 1:50; further preferably, 1:20.
步骤(d)中，所述取代反应的温度为80℃～100℃；优选地，为80℃、90℃、100℃；进一步优选地，为80℃。In the step (d), the temperature of the substitution reaction is from 80 ° C to 100 ° C; preferably, 80 ° C, 90 ° C, 100 ° C; more preferably, 80 ° C.
步骤(d)中，所述取代反应的时间为12～36小时；优选地，为12小时、24小时、36小时；进一步优选地为，12小时。In the step (d), the substitution reaction is carried out for 12 to 36 hours; preferably, 12 hours, 24 hours, 36 hours; further preferably 12 hours.
步骤(d)中，所述取代反应中，所述有机溶剂选自甲醇、甲醇/四氢呋喃、乙醇/四氢呋喃、甲醇/N,N-二甲基甲酰胺、N,N-二甲基甲酰胺；优选地，为甲醇/四氢呋喃(体积比1:1)、乙醇/四氢呋喃(体积比1:3)、甲醇/N,N-二甲基甲酰胺(体积比1:3)；进一步优选地，为甲醇/N,N-二甲基甲酰胺(体积比1:3)。In the step (d), in the substitution reaction, the organic solvent is selected from the group consisting of methanol, methanol/tetrahydrofuran, ethanol/tetrahydrofuran, methanol/N,N-dimethylformamide, and N,N-dimethylformamide; Preferably, it is methanol/tetrahydrofuran (1:1 by volume), ethanol/tetrahydrofuran (volume ratio 1:3), methanol/N,N-dimethylformamide (volume ratio 1:3); further preferably, Methanol / N, N-dimethylformamide (1:3 by volume).
步骤(d)中，所述取代反应中，式(4)化合物，三乙胺和四三苯基膦钯的摩尔比为1:3:(0.05～0.2)；优选地，为1:3:0.05、1:3:0.1、1:3:0.2；进一步优选地，为1:3:0.1。In the step (d), in the substitution reaction, the molar ratio of the compound of the formula (4), triethylamine and tetrakistriphenylphosphine palladium is 1:3:(0.05 to 0.2); preferably, 1:3: 0.05, 1:3:0.1, 1:3:0.2; further preferably, 1:3:0.1.
步骤(d)中，所述取代反应优选在一氧化碳氛围下进行。In the step (d), the substitution reaction is preferably carried out under a carbon monoxide atmosphere.
步骤(e)中，所述还原反应的温度为0℃～50℃；优选地，为0℃、25℃、50℃；优选地，为25℃。In the step (e), the temperature of the reduction reaction is from 0 ° C to 50 ° C; preferably, 0 ° C, 25 ° C, 50 ° C; preferably, 25 ° C.
步骤(e)中，所述还原反应的时间为5小时～10小时；优选地，为5小时、8小时、10小时；进一步优选地为，8小时。In the step (e), the reduction reaction time is 5 hours to 10 hours; preferably, 5 hours, 8 hours, 10 hours; further preferably, 8 hours.
步骤(e)中，所述还原反应中，有机溶剂选自甲醇、乙酸乙酯、乙醇、四氢呋喃；优选地，为甲醇。In the step (e), in the reduction reaction, the organic solvent is selected from the group consisting of methanol, ethyl acetate, ethanol, and tetrahydrofuran; preferably, methanol.
步骤(e)中，所述还原反应中，式(5)化合物、三乙胺和钯/碳的摩尔比为1:5:(0.1～0.5)；优选地，为1:5:0.1、1:5:0.2、1:5:0.5；进一步优选地，为1:5:0.2。In the step (e), in the reduction reaction, the molar ratio of the compound of the formula (5), triethylamine and palladium/carbon is 1:5: (0.1 to 0.5); preferably, 1:5:0.1, 1 : 5: 0.2, 1: 5: 0.5; further preferably, 1: 5: 0.2.
步骤(f)中，所述取代反应的温度为80℃～100℃；优选地，为80℃、90℃、100℃；进一步优选地，为80℃。In the step (f), the temperature of the substitution reaction is from 80 ° C to 100 ° C; preferably, 80 ° C, 90 ° C, 100 ° C; more preferably, 80 ° C.
步骤(f)中，所述取代反应的时间为30分钟～2小时；优选地，为30分钟、1小时、2小时；进一步优选地为，30分钟。 In the step (f), the substitution reaction time is 30 minutes to 2 hours; preferably, 30 minutes, 1 hour, 2 hours; further preferably, 30 minutes.
步骤(f)中，所述取代反应中，有机溶剂选自苯、甲苯、二甲苯、四氢呋喃；优选地为，甲苯。In the step (f), in the substitution reaction, the organic solvent is selected from the group consisting of benzene, toluene, xylene, and tetrahydrofuran; preferably, toluene.
步骤(f)中，所述取代反应中，式(6)化合物和Lawesson’s试剂的摩尔比为1:(1～1.2)；优选地，为1:1、1:1.1、1:1.2；进一步优选地，为1:1.1。In the step (f), in the substitution reaction, the molar ratio of the compound of the formula (6) to the Lawesson's reagent is 1: (1 to 1.2); preferably, 1:1, 1:1.1, 1:1.2; further preferably Ground, 1:1.1.
步骤(f)中，所述取代反应中，所述Lawesson’s试剂为二(4‐甲氧基苯基)‐1,3‐二硫‐2,4‐二膦烷‐2,4‐二硫化物，其结构式为
Figure PCTCN2017098979-appb-000008
In the step (f), in the substitution reaction, the Lawesson's reagent is bis(4-methoxyphenyl)-1,3-dithio- 2,4-diphosphane-2,4-disulfide. , its structural formula is
Figure PCTCN2017098979-appb-000008
步骤(g)中，所述还原反应的温度为40℃～110℃；优选地，为40℃、100℃、110℃；优选地，为110℃。In the step (g), the temperature of the reduction reaction is from 40 ° C to 110 ° C; preferably, 40 ° C, 100 ° C, 110 ° C; preferably, 110 ° C.
步骤(g)中，所述还原反应的时间为10分钟～2小时；优选地，为10分钟、30分钟、1小时、2小时；进一步优选地为，10分钟。In the step (g), the reduction reaction is carried out for 10 minutes to 2 hours; preferably, 10 minutes, 30 minutes, 1 hour, 2 hours; further preferably, 10 minutes.
步骤(g)中，所述还原反应中，有机溶剂选自二氯甲烷、甲苯、1，2-二氯乙烷、苯；优选地，为甲苯。In the step (g), in the reduction reaction, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,2-dichloroethane, and benzene; preferably, toluene.
步骤(g)中，所述还原反应中，式(7)化合物、二异丙基乙胺和对甲基苯亚黄酰氯胺的摩尔比为1:5:(1～2.5)；优选地，为1:5:1、1:5:2、1:5:2.5；进一步优选地，为1:5:2.5。In the step (g), in the reduction reaction, the molar ratio of the compound of the formula (7), diisopropylethylamine and p-toluene flavonolamine is 1:5: (1 to 2.5); preferably, It is 1:5:1, 1:5:2, 1:5:2.5; further preferably, it is 1:5:2.5.
步骤(h-1)中，所述取代反应的温度为–10℃～25℃；优选地，为–10℃、0℃、25℃；进一步优选地，为0℃。In the step (h-1), the temperature of the substitution reaction is from -10 ° C to 25 ° C; preferably, it is -10 ° C, 0 ° C, 25 ° C; further preferably, it is 0 ° C.
步骤(h-1)中，所述取代反应的时间为1小时～5小时；优选地，为1小时、2小时、3小时、4小时、5小时；进一步优选地为，2小时。In the step (h-1), the substitution reaction time is from 1 hour to 5 hours; preferably, it is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours; further preferably, 2 hours.
步骤(h-1)中，所述取代反应中，有机溶剂选自二氯甲烷、四氢呋喃、1,2-二氯乙烷；优选地为，二氯甲烷。In the step (h-1), in the substitution reaction, the organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, and 1,2-dichloroethane; preferably, dichloromethane.
步骤(h-1)中，所述取代反应中，式(8)化合物与三甲氧基四氟硼酸鎓盐的摩尔比为1:(1～3)；优选地，为1:1、1:2、1:3；进一步优选地，为1:3。In the step (h-1), the molar ratio of the compound of the formula (8) to the cerium salt of trimethoxytetrafluoroborate is 1: (1 to 3); preferably, 1:1, 1: 2, 1:3; further preferably, 1:3.
步骤(h-2)中，所述还原反应的温度为0℃～25℃；优选地，为0℃、25℃；进一步优选地为，25℃。In the step (h-2), the temperature of the reduction reaction is from 0 ° C to 25 ° C; preferably, 0 ° C, 25 ° C; further preferably, 25 ° C.
步骤(h-2)中，所述还原反应的时间为30分钟～2小时；优选地，为30分钟、1小时、2小时；进一步优选地为，1小时。In the step (h-2), the reduction reaction time is 30 minutes to 2 hours; preferably, 30 minutes, 1 hour, 2 hours; further preferably, 1 hour.
步骤(h-2)中，所述还原反应中，有机溶剂选自甲醇、二氯甲烷、四氢呋喃、1,2-二氯乙烷；优选地为，甲醇。In the step (h-2), in the reduction reaction, the organic solvent is selected from the group consisting of methanol, dichloromethane, tetrahydrofuran, 1,2-dichloroethane; preferably, methanol.
步骤(h-2)中，所述还原反应中，式(8)化合物与硼氢化钠的摩尔比为1:(5～20)；优 选地，为1:5、1:10、1:20；进一步优选地，为1:10。In the step (h-2), in the reduction reaction, the molar ratio of the compound of the formula (8) to sodium borohydride is 1: (5 to 20); Ground selection is 1:5, 1:10, 1:20; further preferably, 1:10.
步骤(i)中，所述还原反应的温度为0℃～50℃；优选地，为0℃、25℃、50℃；进一步优选地，为25℃。In the step (i), the temperature of the reduction reaction is from 0 ° C to 50 ° C; preferably, 0 ° C, 25 ° C, 50 ° C; further preferably, 25 ° C.
步骤(i)中，所述还原反应的时间为5小时～10小时；优选地，为5小时、8小时、10小时；进一步优选地为，8小时。In the step (i), the reduction reaction time is 5 hours to 10 hours; preferably, 5 hours, 8 hours, 10 hours; further preferably, 8 hours.
步骤(i)中，所述还原反应中，有机溶剂选自甲醇、乙酸乙酯、乙醇、四氢呋喃；优选地，为甲醇。In the step (i), in the reduction reaction, the organic solvent is selected from the group consisting of methanol, ethyl acetate, ethanol, and tetrahydrofuran; preferably, methanol.
步骤(i)中，所述还原反应中，式(4)化合物、三乙胺和钯/碳的摩尔比为1:5:(0.2～0.5)；优选地，为1:5:0.2、1:5:0.5；进一步优选地，为1:5:0.2。In the step (i), in the reduction reaction, the molar ratio of the compound of the formula (4), triethylamine and palladium/carbon is 1:5: (0.2 to 0.5); preferably, 1:5:0.2, 1 : 5: 0.5; further preferably, 1:5: 0.2.
步骤(j)中，所述还原反应的温度为25℃～70℃；优选地，为25℃、50℃、70℃；进一步优选地，为70℃。In the step (j), the temperature of the reduction reaction is from 25 ° C to 70 ° C; preferably, 25 ° C, 50 ° C, 70 ° C; more preferably, 70 ° C.
步骤(j)中，所述还原反应的时间为5小时～15小时；优选地，为5小时、10小时、13小时、15小时；进一步优选地，为13小时。In the step (j), the reduction reaction time is 5 hours to 15 hours; preferably, 5 hours, 10 hours, 13 hours, 15 hours; further preferably, 13 hours.
步骤(j)中，所述还原反应中，所述有机溶剂选自四氢呋喃、甲苯、二氯甲烷；优选地，为四氢呋喃。In the step (j), in the reduction reaction, the organic solvent is selected from the group consisting of tetrahydrofuran, toluene, and dichloromethane; preferably, tetrahydrofuran.
步骤(j)中，所述还原反应中，式(9)化合物与四氢铝锂的摩尔比为1:(5～10)；优选地，1:5、1:10；进一步优选地，为1:10。In the step (j), in the reduction reaction, the molar ratio of the compound of the formula (9) to lithium tetrahydrogenate is 1: (5 to 10); preferably, 1:5, 1:10; further preferably, 1:10.
步骤(k)中，所述还原反应的温度为0℃～50℃；优选地，0℃、25℃、50℃；进一步优选地，为25℃。In the step (k), the temperature of the reduction reaction is from 0 ° C to 50 ° C; preferably, 0 ° C, 25 ° C, 50 ° C; further preferably, 25 ° C.
步骤(k)中，所述还原反应的时间为1小时～3小时；优选地，为1小时、2小时、3小时；进一步优选地为，3小时。In the step (k), the reduction reaction time is from 1 hour to 3 hours; preferably, it is 1 hour, 2 hours, 3 hours; further preferably, 3 hours.
步骤(k)中，所述还原反应中，有机溶剂选自吡啶、三乙胺、2,6-二甲基吡啶；优选地，为吡啶。In the step (k), in the reduction reaction, the organic solvent is selected from the group consisting of pyridine, triethylamine, 2,6-lutidine; preferably, pyridine.
步骤(k)中，所述还原反应中，式(10)化合物、吡啶和乙酸酐的摩尔比为1:(5～10):5；优选地，为1:5:5、1:10:5；进一步优选地，最佳摩尔比为1:10:5。In the step (k), in the reduction reaction, the molar ratio of the compound of the formula (10), pyridine and acetic anhydride is 1: (5-10): 5; preferably, 1:5:5, 1:10: 5; Further preferably, the optimum molar ratio is 1:10:5.
步骤(k)中，所述碱选自吡啶、乙酸钠、三乙胺等中的一种或多种；优选地，为吡啶。In the step (k), the base is one or more selected from the group consisting of pyridine, sodium acetate, triethylamine and the like; preferably, it is a pyridine.
步骤(k)中，所述乙酰化试剂选自乙酸酐、乙酰氯等；优选地，为乙酸酐。In the step (k), the acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride and the like; preferably, acetic anhydride.
在一个具体的实施方式中，本发明不对称合成式(1)化合物(或式(ent-1)化合物)的具体步骤包括： In a specific embodiment, the specific steps of the asymmetric synthesis of a compound of formula (1) (or a compound of formula (ent-1)) of the present invention include:
步骤(a)将式(1a)化合物和式(1b)化合物(或式(ent-1b)化合物)溶于甲苯中，110℃回流反应60小时。减压除去甲苯后直接柱层析得到白色固体式(1c)化合物(或式(ent-1c)化合物)。Step (a) A compound of the formula (1a) and a compound of the formula (1b) (or a compound of the formula (ent-1b)) are dissolved in toluene, and refluxed at 110 ° C for 60 hours. The toluene was removed under reduced pressure and directly subjected to column chromatography to give a white solid (1c) compound (or compound (ent-1c)).
步骤(b)将式(1c)化合物(或式(ent-1c)化合物)溶于三氟乙酸中。室温反应5小时。减压除去三氟乙酸得到褐色油状液体；将此油状液体溶于四氢呋喃和水的混合溶剂中，依次加入碳酸氢钠固体和氯甲酸苄酯，室温下反应15小时。反应液用4N HCl调PH至2-3，减压除掉四氢呋喃。水相用乙酸乙酯萃取5次，无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析分离得到白色固体式(1d)化合物(或式(ent-1d)化合物)。Step (b) A compound of the formula (1c) (or a compound of the formula (ent-1c)) is dissolved in trifluoroacetic acid. The reaction was carried out for 5 hours at room temperature. The trifluoroacetic acid was removed under reduced pressure to give a brown oily liquid. The oily liquid was dissolved in a solvent mixture of tetrahydrofuran and water, and then sodium hydrogencarbonate solid and benzyl chloroacetate were sequentially added and reacted at room temperature for 15 hours. The reaction solution was adjusted to pH 2-3 with 4N HCl and THF was evaporated under reduced pressure. The aqueous phase was extracted 5 times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated.
步骤(c)将式(1d)化合物(或式(ent-1d)化合物)溶于二氯甲烷中，依次加入醋酸碘苯和碘，200W白炽灯的照射下室温反应2小时。然后撤掉白炽灯，加入三乙基硅氢，室温反应30分钟。减压除去甲苯后直接柱层析得到无色油状液体式(1)化合物(或式(ent-1)化合物)。Step (c) A compound of the formula (1d) (or a compound of the formula (ent-1d)) is dissolved in dichloromethane, and then iodobenzene acetate and iodine are sequentially added, and the mixture is irradiated at room temperature for 2 hours under irradiation with a 200 W incandescent lamp. The incandescent lamp was then removed, triethylsilyl hydrogen was added and reacted at room temperature for 30 minutes. The toluene is removed under reduced pressure, and the residue is directly subjected to column chromatography to give a compound (1) or a compound of formula (1).
在一个具体的实施方式中，本发明合成式(1)化合物的反应路线如路线(1’)所示；In a specific embodiment, the reaction route of the compound of the formula (1) of the present invention is shown by the route (1');
Figure PCTCN2017098979-appb-000009
Figure PCTCN2017098979-appb-000009
在一个具体的实施方式中，本发明不对称合成白坚木属生物碱的具体步骤包括：In a specific embodiment, the specific steps of the asymmetric synthesis of the Alkaloids of the present invention include:
步骤(a)将式(1)化合物溶于甲苯中，–78℃下通过自动进样泵历时30分钟加入二异丁基氢化铝，反应升至–40℃搅拌3小时。饱和酒石酸钾钠溶液淬灭反应，室温下搅拌至反应液澄清。减压除掉甲苯，水相用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压除掉溶剂得到无色油状液体。将此油状液体溶于甲苯中，加入Ph3P＝CHCO2R1，其中R1可以是甲基或者乙基，反应升至110℃回流4小时。减压除去甲苯后得到白色固体式(2)化合物。Step (a) The compound of the formula (1) was dissolved in toluene, and diisobutylaluminum hydride was added at -78 ° C for 30 minutes through an auto-injection pump, and the reaction was stirred at -40 ° C for 3 hours. The reaction was quenched with saturated sodium potassium tartrate solution and stirred at room temperature until the reaction mixture was clarified. The toluene was removed under reduced pressure, and the aqueous layer was evaporated. This oily liquid was dissolved in toluene, and Ph 3 P=CHCO 2 R 1 was added , wherein R1 was a methyl group or an ethyl group, and the reaction was refluxed to 110 ° C for 4 hours. The toluene was removed under reduced pressure to give a white solid compound (2).
步骤(b)将式(2)化合物溶于二氯甲烷中，0℃下加入戴斯-马丁氧化剂，反应升至室温搅拌1小时。反应完毕，依次加入饱和硫代硫酸钠溶液和饱和碳酸氢钠溶液，体系用二氯甲烷萃取，无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析分离得到白色泡沫式(3)化合物。 Step (b) The compound of the formula (2) was dissolved in dichloromethane, and Dess-Martin periodinane was added at 0 ° C, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the saturated sodium thiosulfate solution and the saturated sodium hydrogencarbonate solution were successively added, the system was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Compound.
步骤(c)将式(3)化合物溶于甲苯中，依次加入4A分子筛，碳酸钠和ArNHNH2，其中ArNHNH2可以是苯肼，2-甲氧基苯肼，3-甲氧基苯肼或者2,3-二甲氧基苯肼。反应升至110℃回流12小时然后加入同等量的碳酸钠和ArNHNH2，减压除去甲苯后溶于1,2-二氯乙烷中，加入三氟乙酸，反应升至80℃回流1小时，加入饱和碳酸氢钠溶液，二氯甲烷萃取，无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析分离得到淡黄色固体式(4)化合物。Step (c) dissolving the compound of formula (3) in toluene, sequentially adding 4A molecular sieve, sodium carbonate and ArNHNH 2 , wherein ArNHNH 2 may be benzoquinone, 2-methoxyphenylhydrazine, 3-methoxyphenylhydrazine or 2,3-dimethoxybenzoquinone. The reaction was refluxed to 110 ° C for 12 hours, then the same amount of sodium carbonate and ArNHNH 2 was added, toluene was removed under reduced pressure , and then dissolved in 1,2-dichloroethane, trifluoroacetic acid was added, and the reaction was refluxed to 80 ° C for 1 hour. A saturated sodium hydrogencarbonate solution was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated.
步骤(d)将式(4)化合物溶于甲醇/N,N-二甲基甲酰胺(1：3)中，25℃下加入三乙胺和四三苯基膦钯，反应升至80℃搅拌12小时。饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析得到到淡黄色固体式(5)化合物。Step (d) The compound of the formula (4) is dissolved in methanol/N,N-dimethylformamide (1:3), and triethylamine and tetrakistriphenylphosphine palladium are added at 25 ° C, and the reaction is raised to 80 ° C. Stir for 12 hours. The reaction was quenched with aq. EtOAc (EtOAc)EtOAc.
步骤(e)将式(5)化合物溶于甲醇中,依次加入三乙胺和Pd/C。反应瓶用氢气置换后在氢气氛围(氢气球)下搅拌8小时，过滤，乙酸乙酯洗涤滤饼。减压除掉溶剂，柱层析分离得到白色固体式(6)化合物。Step (e) The compound of the formula (5) is dissolved in methanol, and triethylamine and Pd/C are sequentially added. The reaction flask was replaced with hydrogen and stirred under a hydrogen atmosphere (hydrogen balloon) for 8 hours, filtered, and the filter cake was washed with ethyl acetate. The solvent was removed under reduced pressure and purified by column chromatography to yield white compound (6).
步骤(f)将式(6)化合物溶于甲苯中，25℃下加入Lawesson’s试剂，反应升至80℃反应30分钟。反应完毕，冷却至室温，向反应体系加入饱和氯化钠溶液淬灭反应，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析得到到淡黄色固体式(7)化合物。Step (f) The compound of the formula (6) is dissolved in toluene, and Lawesson's reagent is added at 25 ° C, and the reaction is raised to 80 ° C for 30 minutes. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was diluted with a saturated sodium chloride solution, and the mixture was evaporated. The compound of formula (7) is obtained as a pale yellow solid.
步骤(g)将式(7)化合物溶于甲苯中，室温下加入N,N-二异丙基乙胺，氮气氛围下加入新制备的对甲基苯亚黄酰氯，反应升至110℃回流10分钟。减压除掉溶剂，柱层析分离得到淡黄色固体式(8)化合物。Step (g) The compound of the formula (7) is dissolved in toluene, N,N-diisopropylethylamine is added at room temperature, and the newly prepared p-tolueneoxyl chloride is added under a nitrogen atmosphere, and the reaction is refluxed to 110 ° C. 10 minutes. The solvent was removed under reduced pressure and purified by column chromatography to yield a pale yellow solid compound (8).
步骤(h)将式(8)化合物溶于二氯甲烷中，0℃下加入三甲氧基四氟硼酸盐。在0℃下反应2小时，向反应体系加入甲醇，搅拌15分钟后，加入硼氢化钠。在0℃下反应30分钟。反应液用饱和碳酸氢钠溶液淬灭.二氯甲烷萃取.合并有机相无水硫酸钠干燥，过滤，减压除去溶剂，柱层析得到白色固体(-)-16-methoxytabersonine。Step (h) The compound of the formula (8) is dissolved in dichloromethane, and trimethoxytetrafluoroborate is added at 0 °C. The reaction was carried out at 0 ° C for 2 hours, methanol was added to the reaction system, and after stirring for 15 minutes, sodium borohydride was added. The reaction was carried out at 0 ° C for 30 minutes. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc.
步骤(i)将式(4)化合物溶于甲醇中，室温下依次加入三乙胺和Pd/C。反应瓶用氢气置换后在氢气氛围(氢气球)下搅拌8小时，过滤，乙酸乙酯洗涤滤饼。减压除掉溶剂得到白色固体。Step (i) The compound of the formula (4) is dissolved in methanol, and triethylamine and Pd/C are sequentially added at room temperature. The reaction flask was replaced with hydrogen and stirred under a hydrogen atmosphere (hydrogen balloon) for 8 hours, filtered, and the filter cake was washed with ethyl acetate. The solvent was removed under reduced pressure to give a white solid.
步骤(j)将白色固体溶于四氢呋喃中，0℃下加入四氢铝锂，反应升至70℃回流12小时，反应完毕冷却至0℃，反应依次用水，15％氢氧化钠水溶液和水淬灭，过滤，乙酸乙酯洗涤滤饼，减压除去溶剂，柱层析得到白色油固体(-)-Aspidospermidine。Step (j) Dissolve the white solid in tetrahydrofuran, add lithium tetrahydrogenate at 0 ° C, and reflux to 70 ° C for 12 hours. The reaction is cooled to 0 ° C. The reaction is sequentially quenched with water, 15% aqueous sodium hydroxide and water. The mixture was filtered, and the filtrate was washed with ethyl acetate. The solvent was evaporated under reduced pressure and purified to afford white oil (-)-Aspidospermidine.
步骤(k)将(-)-Aspidospermidine溶于吡啶中，室温下加入乙酸酐。室温下搅拌3小时，反应体系用氨水淬灭，二氯甲烷萃取，合并有机相无水硫酸钠干燥，过滤，减压除去溶剂， 柱层析得到无色液体(+)-N-Acetylaspidospermidine。Step (k) Dissolve (-)-Aspidospermidine in pyridine and add acetic anhydride at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was quenched with aqueous EtOAc. Column chromatography gave the colorless liquid (+)-N-Acetylaspidospermidine.
在一个具体的实施方式中，本发明不对称合成白坚木属生物碱的方法如路线(2’)所示；In a specific embodiment, the method for asymmetrically synthesizing Alkaloids of the present invention is as shown in Scheme (2');
Figure PCTCN2017098979-appb-000010
Figure PCTCN2017098979-appb-000010
本发明还提出了一类生物碱化合物，其结构如式(1c)、式(1d)、式(1)、式(ent-1c)、式(ent-1d)、式(ent-1)所示：The present invention also provides a class of alkaloid compounds having the structure of formula (1c), formula (1d), formula (1), formula (ent-1c), formula (ent-1d), and formula (ent-1). Show:
Figure PCTCN2017098979-appb-000011
Figure PCTCN2017098979-appb-000011
Figure PCTCN2017098979-appb-000012
Figure PCTCN2017098979-appb-000012
本发明还提出了一系列白坚木属生物碱化合物，其结构如式(2)、式(3)、式(4)、式(5)、式(6)、式(7)、式(8)、式(9)所示：The present invention also proposes a series of A. sylvestris alkaloid compounds having the structure of formula (2), formula (3), formula (4), formula (5), formula (6), formula (7), formula ( 8), formula (9):
Figure PCTCN2017098979-appb-000013
Figure PCTCN2017098979-appb-000013
其中，R1选自烷基；优选地，为C1-C20烷基；进一步优选地，为C1-C10烷基；进一步优选地，为甲基、乙基、异丙基、叔丁基；进一步优选地，为甲基。Wherein, R 1 is selected from alkyl; preferably, C1-C20 alkyl; more preferably, C1-C10 alkyl; more preferably, methyl, ethyl, isopropyl, tert-butyl group; further Preferably, it is a methyl group.
R2选自氢、烷基、三氟甲基、烷氧基、卤素；进一步优选地，为氢、C1-C20烷基、三氟甲基、C1-C20烷氧基、卤素；进一步优选地，为氢、C1-C10烷基、三氟甲基、C1-C10烷氧基、卤素；进一步优选地，氢、甲基、三氟甲基、甲氧基、氟、氯、溴、碘；进一步优选地为氢、甲氧基。R 2 is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, alkoxy, halogen; further preferably, hydrogen, C1-C20 alkyl, trifluoromethyl, C1-C20 alkoxy, halogen; further preferably Is hydrogen, C1-C10 alkyl, trifluoromethyl, C1-C10 alkoxy, halogen; further preferably, hydrogen, methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, iodo; Further preferred is hydrogen or methoxy.
本发明还提出了所述式(10)～式(12)所示的白坚木属生物碱、式(1c)、式(1d)、式(1)、式(ent-1c)、式(ent-1d)、式(ent-1)或式(2)～式(9)所示的生物碱化合物在制备白坚木属生物碱中的应用。The present invention also provides the alkaloids of the formula (10) to (12), the formula (1c), the formula (1d), the formula (1), the formula (ent-1c), and the formula ( The use of the alkaloid compound represented by ent-1d), formula (ent-1) or formula (2) to formula (9) for the preparation of albino alkaloids.
本发明的有益效果在于，本发明提供的一种高效便捷的不对称合成白坚木属生物碱的方法，从大量可得的以式(1a)化合物和式(1b)化合物出发合成一些白坚木属生物碱，合成路线短，无需高功率反应器、损耗低，条件简单，操作方便，收率较高(2％-5％)，制备的化合物为光学纯化合物。为后续实现该类天然产物的规模化生产及构效关系研究提供良好的技 术支持。The invention has the beneficial effects of the present invention, which provides an efficient and convenient method for asymmetrically synthesizing the alkaloids of the genus Bacillus, and synthesizes some white saponins from a large number of compounds of the formula (1a) and the compound of the formula (1b). Wood alkaloids, short synthetic route, no high-power reactor, low loss, simple conditions, convenient operation, high yield (2%-5%), the prepared compound is optically pure compound. Provide good technology for the subsequent realization of large-scale production and structure-activity relationship research of such natural products Support.
具体实施方式detailed description
结合以下具体实施例，对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。The invention will be further described in detail in conjunction with the following specific examples. The processes, conditions, experimental methods, and the like of the present invention are generally known in the art and common general knowledge, except for the contents specifically mentioned below, and the present invention is not particularly limited.
实施例1Example 1
式(1c)化合物的合成Synthesis of the compound of formula (1c)
Figure PCTCN2017098979-appb-000014
Figure PCTCN2017098979-appb-000014
将式(1a)化合物(8.36g,41.18mmol,1.0equiv.)和式(1b)化合物(16.64g,61.76mmol,1.5equiv.)溶于甲苯(206mL)中，110℃回流反应60小时。减压除去甲苯后直接柱层析(石油醚:乙酸乙酯＝20:1)得到白色固体式(1c)化合物(10.40g,54％yield)，另外回收原料式(1a)化合物(2.56g)。The compound of the formula (1a) (8.36 g, 41.18 mmol, 1.0 equiv.) and the compound of the formula (1b) (16.64 g, 61.76 mmol, 1.5 equiv.) were dissolved in toluene (206 mL) and refluxed at 110 ° C for 60 hours. After removing the toluene under reduced pressure, the residue was purified by column chromatography (ethyl ether: ethyl acetate = 20:1) to give the compound (1.10g, 54% yield) as a white solid, and the compound (1. .
式(1c)化合物的检测数据如下：1H NMR(400MHz,CDCl3)δ6.39(s,1H),4.74(s,1H),4.30(t,J＝10.8Hz,2H),3.08(d,J＝7.2Hz,1H),2.40(dd,J＝22.9,9.7Hz,1H),2.00–1.85(m,3H),1.44(s,9H),1.39(s,9H),1.02(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ172.3,171.1,156.0,133.0,122.3,81.7,80.9,80.4,65.3,64.8,58.3,42.4,27.9,23.3,9.6.IR(neat,cm-1)2925,1763,1736,1460,1227,1152,1044.HRMS(ESI)[M+NH4]+Calcd for C21H34BrN2O6489.1595,Found 489.1595.[α]D 25+129.5(c 1.0,CHCl3),ent-1c:[α]D 25-115.4(c 1.0,CHCl3).Formula (1c) detecting data of the compound are as follows: 1 H NMR (400MHz, CDCl 3) δ6.39 (s, 1H), 4.74 (s, 1H), 4.30 (t, J = 10.8Hz, 2H), 3.08 (d , J = 7.2 Hz, 1H), 2.40 (dd, J = 22.9, 9.7 Hz, 1H), 2.00 - 1.85 (m, 3H), 1.44 (s, 9H), 1.39 (s, 9H), 1.02 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 172.3, 171.1, 156.0, 133.0, 122.3, 81.7, 80.9, 80.4, 65.3, 64.8, 58.3, 42.4, 27.9, 23.3, 9.6. IR (neat , cm -1 ) 2925,1763,1736,1460,1227,1152,1044.HRMS(ESI)[M+NH 4 ] + Calcd for C 21 H 34 BrN 2 O 6 489.1595,Found 489.1595.[α] D 25 +129.5 (c 1.0, CHCl 3 ), ent-1c: [α] D 25 -115.4 (c 1.0, CHCl 3 ).
实施例2Example 2
式(1d)化合物的合成Synthesis of the compound of formula (1d)
Figure PCTCN2017098979-appb-000015
Figure PCTCN2017098979-appb-000015
将式(1c)化合物(10.40g,22.02mmol,1.0equiv.)溶于三氟乙酸(20mL)中。室温反应5小时。减压除去三氟乙酸得到褐色油状液体(无需柱层析分离纯化)；The compound of formula (1c) (10.40 g, 22.02 mmol, 1.0 equiv.) was dissolved in trifluoroacetic acid (20 mL). The reaction was carried out for 5 hours at room temperature. The trifluoroacetic acid was removed under reduced pressure to give a brown oily liquid (purified without column chromatography);
将此油状液体溶于四氢呋喃(140mL)和水(70mL)的混合溶剂中，依次加入碳酸氢钠固体(37.34g,440.33mmol,20.0equiv.)和氯甲酸苄酯(18.77g,110.08mmol,5.0equiv.)，室温下反应15小时。反应液用4N HCl调PH至2-3，减压除掉四氢呋喃。水相用乙酸乙酯萃取5次， 无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析分离(石油醚:乙酸乙酯＝2:1)得到白色固体式(1d)化合物(6.48g,66％yield for two steps)。This oily liquid was dissolved in a mixed solvent of tetrahydrofuran (140 mL) and water (70 mL), and then sodium hydrogencarbonate solid (37.34 g, 440.33 mmol, 20.0 equiv.) and benzyl chloroformate (18.77 g, 110.08 mmol, 5.0 Equiv.), react at room temperature for 15 hours. The reaction solution was adjusted to pH 2-3 with 4N HCl and THF was evaporated under reduced pressure. The aqueous phase was extracted 5 times with ethyl acetate. The residue was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
式(1d)化合物的检测数据如下：1H NMR(400MHz,CDCl3)δ7.22(d,J＝18.3Hz,4H),6.34(s,1H),5.94(s,1H),4.99(s,2H),4.73(s,1H),4.49(d,J＝7.4Hz,1H),4.30(d,J＝9.4Hz,1H),3.07(dd,J＝17.5,8.5Hz,1H),2.43(dt,J＝13.8,9.1Hz,1H),2.14–1.98(m,1H),1.90(s,1H),0.96(s,3H).13C NMR(100MHz,CDCl3)δ177.3,170.9,156.4,135.3,132.7,128.5,128.3,128.1,122.6,80.6,68.0,64.7,63.9,58.0,42.8,28.4,23.2,9.5.IR(neat,cm-1)2925,1753,1394,1257,1185,1087,1009.HRMS(ESI)[M+NH4]+Calcd for C20H24BrN2O6 467.0812,Found467.0812.[α]D 25+118.0(c 1.0,CHCl3)ent-1d:[α]D 25-109.9(c 0.5,CHCl3).The test data for the compound of formula (1d) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, J = 18.3 Hz, 4H), 6.34 (s, 1H), 5.94 (s, 1H), 4.99 (s , 2H), 4.73 (s, 1H), 4.49 (d, J = 7.4 Hz, 1H), 4.30 (d, J = 9.4 Hz, 1H), 3.07 (dd, J = 17.5, 8.5 Hz, 1H), 2.43 (dt, J = 13.8, 9.1 Hz, 1H), 2.14 - 1.98 (m, 1H), 1.90 (s, 1H), 0.96 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 177.3, 170.9, 156.4 , 135.3, 132.7, 128.5, 128.3, 128.1, 122.6, 80.6, 68.0, 64.7, 63.9, 58.0, 42.8, 28.4, 23.2, 9.5. IR (neat, cm -1 ) 2925, 1753, 1394, 1257, 1185, 1087 , 1009.HRMS (ESI) [M+NH 4 ] + Calcd for C 20 H 24 BrN 2 O 6 467.0812, Found 467.0812. [α] D 25 +118.0 (c 1.0, CHCl 3 )ent-1d: [α ] D 25 -109.9 (c 0.5, CHCl 3 ).
实施例3Example 3
式(1)化合物的合成Synthesis of compounds of formula (1)
Figure PCTCN2017098979-appb-000016
Figure PCTCN2017098979-appb-000016
将式(1)化合物(6.48g,14.43mmol,1.0equiv.)溶于新蒸的二氯甲烷(140mL)中，依次加入醋酸碘苯(9.30g,28.86mmol,2.0equiv.)和碘(0.73g,2.89mmol,0.2equiv.)，200W白炽灯的照射下室温反应2小时。然后撤掉白炽灯，加入三乙基硅氢(8.37g,72.15mmol,5.0equiv.)，室温反应30分钟。减压除去甲苯后直接柱层析(石油醚:乙酸乙酯＝20:1)得到无色油状液体式(1)化合物(5.38g,92％yield)。The compound of the formula (1) (6.48 g, 14.43 mmol, 1.0 equiv.) was dissolved in freshly distilled dichloromethane (140 mL), followed by the addition of iodobenzene (9.30 g, 28.86 mmol, 2.0 equiv.) and iodine (0.73) g, 2.89 mmol, 0.2 equiv.), 200 W incandescent lamp was irradiated at room temperature for 2 hours. The incandescent lamp was then removed and triethylsilicohydrogen (8.37 g, 72.15 mmol, 5.0 equiv.) was added and allowed to react at room temperature for 30 minutes. After the toluene was removed under reduced pressure, the title compound (5.38 g, 92% yield) was obtained as a colorless oil.
式(1)化合物的检测数据如下：1H NMR(400MHz,CDCl3)δ7.38–7.29(m,5H),6.38(s,1H),5.10(dd,J＝29.0,12.2Hz,2H),4.94(t,J＝1.9Hz,1H),4.21(d,J＝211.6Hz,2H),3.23(td,J＝11.6,7.3Hz,1H),2.93(t,J＝9.6Hz,1H),2.16–1.87(m,3H),1.81(s,1H),1.02(m,3H).13C NMR(100MHz,CDCl3)δ171.8,155.6,136.0,131.6,128.4,128.1,127.8,122.6,83.8,67.5,61.5,56.2,47.0,43.1,28.2,22.2,8.8.IR(neat,cm-1)2926,1759,1702,1407,1259,1196,1095,1011.HRMS(ESI)[M+NH4]+Calcd for C19H24BrN2O4 423.0914,Found 423.0912.[α]D 25+101.4(c 1.0,CHCl3),ent-1:[α]D 25-98.2(c 1.0,CHCl3).The test data for the compound of formula (1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 - 7.29 (m, 5H), 6.38 (s, 1H), 5.10 (dd, J = 29.0, 12.2 Hz, 2H) , 4.94 (t, J = 1.9 Hz, 1H), 4.21 (d, J = 211.6 Hz, 2H), 3.23 (td, J = 11.6, 7.3 Hz, 1H), 2.93 (t, J = 9.6 Hz, 1H) , 2.16–1.87 (m, 3H), 1.81 (s, 1H), 1.02 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 171.8, 155.6, 136.0, 131.6, 128.4, 128.1, 127.8, 122.6, 83.8 , 67.5, 61.5, 56.2, 47.0, 43.1, 28.2, 22.2, 8.8. IR (neat, cm -1 ) 2926, 1759, 1702, 1407, 1259, 1196, 1095, 1011. HRMS (ESI) [M+NH 4 ] + Calcd for C 19 H 24 BrN 2 O 4 423.0914, Found 423.0912. [α] D 25 +101.4 (c 1.0, CHCl 3 ), ent-1: [α] D 25 -98.2 (c 1.0, CHCl 3 ) .
实施例4Example 4
式(2a)化合物的合成 Synthesis of the compound of formula (2a)
Figure PCTCN2017098979-appb-000017
Figure PCTCN2017098979-appb-000017
将式(1)化合物(4.09g,2.61mmol,1.0equiv.)溶于甲苯(100mL)中，–78℃下通过自动进样泵历时30分钟加入二异丁基氢化铝(10mL,3.91mmol,1.5equiv.,1.5M in toluene)反应升至–40℃搅拌3小时。饱和酒石酸钾钠溶液(20mL)淬灭反应，室温下搅拌至反应液澄清。减压除掉甲苯，水相用乙酸乙酯(3x 50mL)萃取，无水硫酸钠干燥，过滤，减压除掉溶剂得到无色油状液体(无需柱层析分离纯化)。The compound of the formula (1) (4.09 g, 2.61 mmol, 1.0 equiv.) was dissolved in toluene (100 mL), and diisobutylaluminum hydride (10 mL, 3.91 mmol) was added at -78 °C through an auto-injection pump over 30 minutes. 1.5 equiv., 1.5 M in toluene) The reaction was stirred at -40 ° C for 3 hours. The reaction was quenched with saturated sodium potassium tartrate solution (20 mL) and stirred at room temperature until the reaction mixture was clarified. The toluene was removed under reduced pressure, the aqueous layer was evaporated, evaporated, evaporated, evaporated, evaporated
将此油状液体溶于甲苯(100mL)中，加入Ph3P＝CHCO2Me(5.05g,3.41mmol,1.5equiv。)，反应升至110℃回流4小时。减压除去甲苯后直接柱层析(石油醚:乙酸乙酯＝3:1)得到白色固体式(2a)化合物(3.55g,76％yield for two steps)。This oily liquid was dissolved in toluene (100 mL), and Ph 3 P=CHCO 2 Me (5.05 g, 3.41 mmol, 1.5 equiv.) was added, and the reaction was refluxed to 110 ° C for 4 hours. The toluene was removed under reduced pressure and purified by column chromatography (ethyl ether: ethyl acetate = 3:1) to yield white solid (2a) compound (3.55 g, 76% yield for two steps).
式(2a)化合物的检测数据如下：1H NMR(400MHz,CDCl3)δ7.38–7.35(m,5H),6.91(d,J＝16.1Hz,1H),5.94(s,1H),5.78(dd,J＝32.9,16.7Hz,2H),5.15(d,J＝4.8Hz,1H),4.54(d,J＝6.9Hz,1H),4.36(d,J＝6.7Hz,1H),3.71(s,3H),3.41(dd,J＝18.5,10.6Hz,1H),3.31–3.22(m,1H),2.73–2.65(m,1H),2.09–2.02(m,1H),1.99–1.61(m,2H),0.86(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ166.5,155.6,153.1,136.7,132.1,128.5,127.9,127.6,120.6,68.0,67.0,60.9,48.9,45.2,44.0,33.3,25.2,8.5.旋转异构体:1H NMR(400MHz,CDCl3)δ7.32–7.29(m,5H),6.81(d,J＝16.0Hz,1H),5.21–5.09(m,2H),4.50(d,J＝7.1Hz,1H),4.27(d,J＝6.6Hz,1H),3.71(s,3H),3.50(dd,J＝19.0,10.3Hz,1H),3.31–3.22(m,1H),2.73–2.65(m,1H),2.09–2.02(m,1H),1.97–1.61(m,3H),1.41(td,J＝14.4,7.3Hz,1H),0.67(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ166.4,154.8,152.6,136.1,128.5,128.3,127.2,127.0,120.8,67.6,60.1,51.6,48.7,45.5,44.6,32.4,24.3,8.3.IR(neat,cm-1)3396,2925,1701,1414,1257,1009.HRMS(ESI)[M+NH4]+Calcd for C22H30BrN2O5 481.1333,Found 481.1332.[α]D 25+94.6(c 1.0,CHCl3).The test data for the compound of the formula (2a) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 - 7.35 (m, 5H), 6.91 (d, J = 16.1 Hz, 1H), 5.94 (s, 1H), 5.78 (dd, J = 32.9, 16.7 Hz, 2H), 5.15 (d, J = 4.8 Hz, 1H), 4.54 (d, J = 6.9 Hz, 1H), 4.36 (d, J = 6.7 Hz, 1H), 3.71 (s, 3H), 3.41 (dd, J = 18.5, 10.6 Hz, 1H), 3.31 - 3.22 (m, 1H), 2.73 - 2.65 (m, 1H), 2.09 - 2.02 (m, 1H), 1.99 - 1.61 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.5, 155.6, 153.1, 136.7, 132.1, 128.5, 127.9, 127.6, 120.6, 68.0, 67.0, 60.9 , 48.9, 45.2, 44.0, 33.3, 25.2, 8.5. Rotamers: 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 - 7.29 (m, 5H), 6.81 (d, J = 16.0 Hz, 1H), 5.21–5.09 (m, 2H), 4.50 (d, J = 7.1 Hz, 1H), 4.27 (d, J = 6.6 Hz, 1H), 3.71 (s, 3H), 3.50 (dd, J = 19.0, 10.3 Hz) , 1H), 3.31–3.22 (m, 1H), 2.73–2.65 (m, 1H), 2.09–2.02 (m, 1H), 1.97–1.61 (m, 3H), 1.41 (td, J=14.4, 7.3 Hz , 1H), 0.67 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.4, 154.8, 152.6, 136.1, 128.5, 128.3, 127.2, 127.0, 120.8, 67.6, 60.1, 51.6, 48.7 , 45.5, 44.6, 32.4, 24.3, 8.3. IR (neat, cm -1 ) 3396, 2925, 1701, 1414, 1257, 1009. HRMS (ESI) [M+NH 4 ] + Calcd for C 22 H 30 BrN 2 O 5 481.1333, Foun d 481.1332. [α] D 25 +94.6 (c 1.0, CHCl 3 ).
实施例5Example 5
式(3a)化合物的合成 Synthesis of Compound of Formula (3a)
Figure PCTCN2017098979-appb-000018
Figure PCTCN2017098979-appb-000018
将式(2a)化合物(3.55g,7.65mmol,1.0equiv.)溶于二氯甲烷中(76mL)中，0℃下加入戴斯-马丁氧化剂(3.89g,9.17mmol,1.2equiv.)，反应升至室温搅拌1小时。反应完毕，依次加入饱和硫代硫酸钠溶液(25mL)和饱和碳酸氢钠溶液(25mL)，体系用二氯甲烷(3x 50mL)萃取无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析分离(石油醚:乙酸乙酯＝10:1)得到白色泡沫式(3a)化合物(3.23g,92％)。The compound of the formula (2a) (3.55 g, 7.65 mmol, 1.0 equiv.) was dissolved in dichloromethane (76 mL), and then, at 0 ° C, Dess-Martin oxidant (3.89 g, 9.17 mmol, 1.2 equiv.) was added. Stir to room temperature and stir for 1 hour. After completion of the reaction, a saturated sodium thiosulfate solution (25 mL) and a saturated sodium hydrogen carbonate solution (25 mL) were successively added, and the mixture was dried over anhydrous sodium sulfate (dichloromethane) (3×50 mL), filtered, and the solvent was removed under reduced pressure. The title compound (3.23 g, 92%) was obtained.
式(3a)化合物的检测数据如下：1H NMR(500MHz,CDCl3)δ7.38–7.35(m,5H),7.15(s,1H),6.99(d,J＝16.2Hz,1H),5.73(d,J＝16.2Hz,1H),5.19(s,1H),5.14–5.10(m,1H),4.70(d,J＝7.8Hz,1H),3.73(s,3H),3.61–3.53(m,1H),3.47–3.39(m,1H),3.09(dt,J＝12.8,8.3Hz,1H),2.35–2.24(m,1H),2.04–1.87(m,2H),1.82–1.73(m,1H),1.00(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ189.8,166.0,155.9,151.3,136.1,128.5,127.8,124.2,122.4,67.4,61.6,51.8,50.5,48.2,46.0,31.6,28.9,8.6.旋转异构体1H NMR(500MHz,CDCl3)δ7.35–7.32(m,5H),7.05(s,1H),6.92(d,J＝16.2Hz,1H),5.69(d,J＝16.2Hz,1H),5.21(s,1H),5.12–5.09(m,1H),4.60(d,J＝7.8Hz,1H),3.73(s,3H),3.70–3.64(m,1H),3.47–3.39(m,1H),3.09(dt,J＝12.8,8.3Hz,1H),2.35–2.24(m,1H),2.04–1.87(m,2H),1.82–1.73(m,1H),1.00(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ189.7,165.8,155.1,151.1,150.9,135.5,128.8,128.2,124.4,122.4,68.0,60.8,51.8,50.1,48.9,46.3,31.1,27.9,8.4.IR(neat,cm-1)2963,2927,1698,1454,1260,1090,1019,799.HRMS(ESI)[M+NH4]+Calcd for C22H28BrN2O5 479.1176,Found 479.1172.[α]D 25+133.0(c 1.0,CHCl3).The test data for the compound of the formula (3a) are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 7.38 - 7.35 (m, 5H), 7.15 (s, 1H), 6.99 (d, J = 16.2 Hz, 1H), 5.73 (d, J = 16.2 Hz, 1H), 5.19 (s, 1H), 5.14 - 5.10 (m, 1H), 4.70 (d, J = 7.8 Hz, 1H), 3.73 (s, 3H), 3.61 - 3.53 ( m,1H), 3.47–3.39 (m,1H), 3.09 (dt, J=12.8, 8.3 Hz, 1H), 2.35–2.24 (m, 1H), 2.04–1.87 (m, 2H), 1.82–1.73 ( m,1H), 1.00 (t, J = 7.0 Hz, 3H). 13 C NMR (125MHz, CDCl 3 ) δ 189.8, 166.0, 155.9, 151.3, 136.1, 128.5, 127.8, 124.2, 122.4, 67.4, 61.6, 51.8, 50.5, 48.2, 46.0, 31.6, 28.9, 8.6. Rotamer 1 H NMR (500 MHz, CDCl 3 ) δ 7.35 - 7.32 (m, 5H), 7.05 (s, 1H), 6.92 (d, J = 16.2 Hz, 1H), 5.69 (d, J = 16.2 Hz, 1H), 5.21 (s, 1H), 5.12 - 5.09 (m, 1H), 4.60 (d, J = 7.8 Hz, 1H), 3.73 (s, 3H) ), 3.70–3.64 (m, 1H), 3.47–3.39 (m, 1H), 3.09 (dt, J = 12.8, 8.3 Hz, 1H), 2.35–2.24 (m, 1H), 2.04–1.87 (m, 2H) ), 1.82 - 1.73 (m, 1H), 1.00 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 189.7, 165.8, 155.1, 151.1, 150.9, 135.5, 128.8, 128.2, 124.4, 122.4, 68.0, 60.8, 51.8, 50.1, 48.9, 46.3, 31.1, 27.9, 8.4. IR (neat, cm -1 ) 2963, 2927, 1698, 1454, 1260, 1090, 1019, 799. HRMS (ESI) [M +NH 4 ] + Calcd for C 22 H 28 BrN 2 O 5 479.1176, Found 479.1172. [α] D 25 +133.0 (c 1.0, CHCl 3 ).
实施例6Example 6
式(4a)化合物的合成Synthesis of the compound of formula (4a)
Figure PCTCN2017098979-appb-000019
Figure PCTCN2017098979-appb-000019
将式(3a)(3.23g,7.01mmol,1.0equiv)，4A,MS(1.26g)，碳酸钠(2.45g,14.02mmol, 2.0equiv.)和3-甲氧基苯肼(1.48g,14.02mmol,2.0equiv.)溶于甲苯(140mL)中，反应升至110℃回流12小时。加入碳酸钠(2.45g,14.02mmol,2.0equiv.)和3-甲氧基苯肼(1.48g,14.02mmol,2.0equiv.)继续反应12小时。反应完毕，冷却至室温，减压除去苯后直接得到褐色固体(无需柱层析分离纯化)。将此褐色固体溶于1,2-二氯乙烷(140mL)中，反应升至80℃加入三氟乙酸(15.96g,140.2mmol,20.0equiv)回流1小时。反应完毕，冷却至室温，用饱和碳酸氢钠溶液调PH至8-9，二氯甲烷(3x 50mL)萃取，无水硫酸钠干燥，过滤，减压除掉溶剂，柱层析分离(石油醚:乙酸乙酯＝10:1)得到淡黄色固体式(4a)化合物(2.16g,55％)，另外回收式(3a)化合物(0.19g)。Formula (3a) (3.23 g, 7.01 mmol, 1.0 equiv), 4A, MS (1.26 g), sodium carbonate (2.45 g, 14.02 mmol, 2.0 equiv.) and 3-methoxyphenylhydrazine (1.48 g, 14.02 mmol, 2.0 equiv.) were dissolved in toluene (140 mL), and the reaction was refluxed to 110 ° C to reflux for 12 hours. The reaction was continued for 12 hours by the addition of sodium carbonate (2.45 g, 14.02 mmol, 2.0 equiv.) and 3-methoxyphenylhydrazine (1.48 g, 14.02 mmol, 2.0 equiv.). After the reaction was completed, it was cooled to room temperature, and benzene was removed under reduced pressure to give a brown solid (purified by column chromatography). The brown solid was dissolved in 1 ,2-dichloroethane (140 mL) and the mixture was taken to <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; After completion of the reaction, it was cooled to room temperature, and the mixture was adjusted to pH 8-9 with aq. sodium hydrogen carbonate, dichloromethane (3×50 mL), dried over anhydrous sodium sulfate, filtered and evaporated Ethyl acetate = 10:1) Compound (4a) (2.16 g, 55%) was obtained as a pale yellow solid, and the compound of formula (3a) (0.19 g) was recovered.
式(4a)化合物的检测数据如下：1H NMR(500MHz,CDCl3)δ7.48–7.29(m,6H),7.06(d,J＝16.1Hz,1H),6.78(d,J＝8.2Hz,1H),6.65(dd,J＝8.2,2.4Hz,1H),6.57(s,1H),5.98(d,J＝16.1Hz,1H),5.27(d,J＝30.9Hz,1H),5.21(d,J＝35.5Hz,1H),4.32(s,1H),3.88(td,J＝11.1,7.8Hz,1H),3.81(s,3H),3.75(s,3H),3.53–3.41(m,1H),2.44–2.35(m,1H),1.98(dq,J＝14.7,7.4Hz,1H),1.86(dq,J＝14.8,7.4Hz,1H),1.76–1.66(m,1H),0.79(t,J＝7.4Hz,3H).13C NMR(125MHz,CDCl3)δ175.4,166.1,160.6,155.2,154.9,151.8,144.5,136.5,134.9,128.6,128.2,127.9,121.4,121.3,114.6,112.9,107.7,67.5,65.6,60.9,55.6,52.5,51.8,44.3,35.8,34.7,8.7.旋转异构体1H NMR(500MHz,CDCl3)δ7.48–7.29(m,6H),6.95(d,J＝16.1Hz,1H),6.88(d,J＝8.2Hz,1H),6.72(dd,J＝8.2,2.4Hz,1H),6.50(s,1H),5.93(d,J＝16.1Hz,1H),5.29(d,J＝30.9Hz,1H),5.18(d,J＝35.5Hz,1H),4.24(s,1H),3.83(s,3H),3.77(s,3H),3.53–3.41(m,1H),2.44–2.35(m,1H),1.76–1.66(m,3H),1.59(dq,J＝14.7,7.4Hz,1H),0.65(t,J＝7.4Hz,3H).13C NMR(125MHz,CDCl3)δ175.2,165.9,160.7,154.9,154.6,151.4,144.2,135.8,135.0,128.6,128.4,127.9,121.5,121.4,114.9,112.9,107.9,67.9,65.3,61.7,55.6,52.3,51.9,44.8,34.8,33.7,8.5.IR(neat,cm-1)2942,1702,1439,1361,1326,1255,960.HRMS(ESI)[M+H]+Calcd for C29H30BrN2O5 565.1333,Found 565.1326.[α]D 25-60.0(c 0.5,CHCl3).The test data for the compound of the formula (4a) are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 7.48 - 7.29 (m, 6H), 7.06 (d, J = 16.1 Hz, 1H), 6.78 (d, J = 8.2 Hz) , 1H), 6.65 (dd, J = 8.2, 2.4 Hz, 1H), 6.57 (s, 1H), 5.98 (d, J = 16.1 Hz, 1H), 5.27 (d, J = 30.9 Hz, 1H), 5.21. (d, J = 35.5 Hz, 1H), 4.32 (s, 1H), 3.88 (td, J = 11.1, 7.8 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.53 - 3.41 ( m,1H), 2.44–2.35 (m,1H), 1.98 (dq, J=14.7, 7.4 Hz, 1H), 1.86 (dq, J=14.8, 7.4 Hz, 1H), 1.76–1.66 (m, 1H) , 0.79 (t, J = 7.4Hz , 3H). 13 C NMR (125MHz, CDCl 3) δ175.4,166.1,160.6,155.2,154.9,151.8,144.5,136.5,134.9,128.6,128.2,127.9,121.4,121.3, 114.6, 112.9, 107.7, 67.5, 65.6, 60.9, 55.6, 52.5, 51.8, 44.3, 35.8, 34.7, 8.7. Rotamer 1 H NMR (500 MHz, CDCl 3 ) δ 7.48 - 7.29 (m, 6H), 6.95 (d, J = 16.1 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.72 (dd, J = 8.2, 2.4 Hz, 1H), 6.50 (s, 1H), 5.93 (d, J) =16.1 Hz, 1H), 5.29 (d, J = 30.9 Hz, 1H), 5.18 (d, J = 35.5 Hz, 1H), 4.24 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H) ), 3.53–3.41 (m, 1H), 2.44–2.35 (m, 1H), 1.76–1.66 (m, 3H), 1.59 (dq, J=14.7, 7.4 Hz, 1H), 0.65 (t, J=7.4) hz, 3H). 13 C NMR (125MHz, CDCl 3) δ175.2,165.9,160.7,154.9,154.6,151.4,1 44.2, 135.8, 135.0, 128.6, 128.4, 127.9, 121.5, 121.4, 114.9, 112.9, 107.9, 67.9, 65.3, 61.7, 55.6, 52.3, 51.9, 44.8, 34.8, 33.7, 8.5. IR (neat, cm -1 ) 2942, 1702, 1439, 1361, 1326, 1255, 960. HRMS (ESI) [M+H] + Calcd for C 29 H 30 BrN 2 O 5 565.1333, Found 565.1326. [α] D 25 -60.0 (c 0.5, CHCl 3 ).
实施例7Example 7
式(5a)化合物的合成 Synthesis of Compound of Formula (5a)
Figure PCTCN2017098979-appb-000020
Figure PCTCN2017098979-appb-000020
将式(4a)化合物(2.79g,4.93mmol,1.0equiv.)溶于甲醇/N,N-二甲基甲酰胺(1/3,48mL)中，室温下加入三乙胺(1.50g,14.8mmol,3.0equiv.)和Pd(PPh3)4(570mg,0.493mmol,0.1equiv.).反应体系用一氧化碳置换并将反应升至80℃反应12小时。反应完毕，冷却至室温，向反应体系中加入饱和氯化铵溶液(50mL).体系用乙酸乙酯((50mL))萃取，有机相用饱和食盐水(3x 50mL)洗，无水硫酸钠干燥，过滤，减压除去溶剂后直接柱层析(石油醚:乙酸乙酯＝5:1)得到淡黄色固体式(5a)化合物(1.88g,70％)，另外回收式(4a)化合物(0.22g)。The compound of the formula (4a) (2.79 g, 4.93 mmol, 1.0 equiv.) was dissolved in methanol/N,N-dimethylformamide (1/3, 48 mL), and triethylamine (1.50 g, 14.8) Methyl, 3.0 equiv.) and Pd(PPh 3 ) 4 (570 mg, 0.493 mmol, 0.1 equiv.). The reaction system was replaced with carbon monoxide and the reaction was allowed to rise to 80 ° C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, and a saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL). After filtration, the solvent was removed under reduced pressure and then purified tolululululululululililililililililililili g).
式(5a)化合物的检测数据如下：1H NMR(500MHz,CDCl3)δ7.44–7.31(m,6H),7.22(s,1H),7.09(d,J＝16.3Hz,1H),6.84(d,J＝8.2Hz,1H),6.66(dd,J＝8.2,2.3Hz,1H),5.92(d,J＝16.2Hz,1H),5.26(d,J＝18.6Hz,1H),5.24(d,J＝18.2Hz,1H),4.25(s,1H),3.94(s,3H),3.92–3.87(m,1H),3.82(s,3H),3.75(s,3H),3.53–3.41(m,1H),2.33–2.21(m,1H),2.01(dq,J＝14.7,7.3Hz,1H),1.90(dq,J＝14.7,7.5Hz,1H),1.80–1.71(m,1H),0.76(t,J＝7.4Hz,3H).旋转异构体1H NMR(500MHz,CDCl3)δ7.44–7.31(m,6H),7.15(s,1H),6.96(d,J＝8.6Hz,1H),6.94(s,1H),6.73(dd,J＝8.2,2.2Hz,1H),5.86(d,J＝16.2Hz,1H),5.30(d,J＝6.5Hz,1H),5.15(d,J＝12.1Hz,1H),4.17(s,1H),3.94(s,3H),3.83(s,3H),3.77(s,3H),3.53–3.41(m,1H),2.33–2.21(m,1H),1.80–1.71(m,3H),1.63(dq,J＝14.7,7.4Hz,1H),0.62(t,J＝7.4Hz,3H).IR(neat,cm-1)3368,2988,2926,1702,1611,1241,1084,736.HRMS(ESI)[M+H]+Calcd for C31H33N2O7 545.2282,Found 545.2277.[α]D 25-80.2(c 0.5,CHCl3).The test data for the compound of the formula (5a) are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 7.44 - 7.31 (m, 6H), 7.22 (s, 1H), 7.09 (d, J = 16.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.66 (dd, J = 8.2, 2.3 Hz, 1H), 5.92 (d, J = 16.2 Hz, 1H), 5.26 (d, J = 18.6 Hz, 1H), 5.24 (d, J = 18.2 Hz, 1H), 4.25 (s, 1H), 3.94 (s, 3H), 3.92 - 3.87 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.53 - 3.41(m,1H), 2.33–2.21(m,1H), 2.01 (dq, J=14.7, 7.3 Hz, 1H), 1.90 (dq, J=14.7, 7.5 Hz, 1H), 1.80–1.71 (m, 1H), 0.76 (t, J = 7.4 Hz, 3H). Rotamer 1 H NMR (500 MHz, CDCl 3 ) δ 7.44 - 7.31 (m, 6H), 7.15 (s, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.94 (s, 1H), 6.73 (dd, J = 8.2, 2.2 Hz, 1H), 5.86 (d, J = 16.2 Hz, 1H), 5.30 (d, J = 6.5 Hz, 1H), 5.15 (d, J = 12.1 Hz, 1H), 4.17 (s, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.53 - 3.41 (m, 1H) ), 2.33–2.21 (m, 1H), 1.80–1.71 (m, 3H), 1.63 (dq, J=14.7, 7.4 Hz, 1H), 0.62 (t, J=7.4 Hz, 3H). IR (neat, Cm -1 ) 3368,2988,2926,1702,1611,1241,1084,736.HRMS(ESI)[M+H] + Calcd for C 31 H 33 N 2 O 7 545.2282,Found 545.2277.[α] D 25 -80.2 (c 0.5, CHCl 3 ).
实施例8Example 8
式(6a)化合物的合成 Synthesis of the compound of formula (6a)
Figure PCTCN2017098979-appb-000021
Figure PCTCN2017098979-appb-000021
将式(5a)化合物(1.80g,3.31mmol,1.0equiv.)溶于甲醇(330mL)中,依次加入三乙胺(1.67g,16.53mmol,5.00equiv.)和Pd/C(10wt％,352mg,0.33mmol,0.10equiv.)。反应瓶用氢气置换后在氢气氛围(氢气球)下搅拌8小时,过滤，乙酸乙酯(3x 50mL)洗涤滤饼。减压除掉溶剂，柱层析分离(石油醚：乙酸乙酯＝1:1)得到白色固体式(6a)化合物(0.87g,69％)。The compound of the formula (5a) (1.80 g, 3.31 mmol, 1.0 equiv.) was dissolved in methanol (330 mL), followed by triethylamine (1.67 g, 16.53 mmol, 5.00 equiv.) and Pd/C (10 wt%, 352 mg). , 0.33 mmol, 0.10 equiv.). The reaction flask was replaced with hydrogen and stirred under a hydrogen atmosphere (hydrogen balloon) for 8 hours, filtered, and ethyl acetate (3×50 mL) washed. The solvent was removed under reduced pressure and purified (EtOAcjjjjjjjjj
式(6a)化合物的检测数据如下：1H NMR(500MHz,CDCl3)δ8.96(s,1H),7.05(d,J＝8.1Hz,1H),6.44(d,J＝2.2Hz,1H),6.42(dd,J＝8.1,2.3Hz,1H),4.13(dd,J＝11.7,7.6Hz,1H),3.78(s,3H),3.77(s,3H),3.41(d,J＝1.6Hz,1H),3.37(td,J＝12.0,5.5Hz,1H),2.63(dd,J＝15.5,1.8Hz,1H),2.37(dt,J＝15.3,4.2Hz,1H),2.27(td,J＝14.2,5.0Hz,1H),2.01–1.92(m,2H),1.89(d,J＝15.5Hz,1H),1.79(dd,J＝12.2,5.4Hz,1H),1.34(td,J＝13.2,4.2Hz,1H),0.98(q,J＝7.3Hz,2H),0.69(t,J＝7.3Hz,3H).13C NMR(125MHz,CDCl3)δ171.6,168.3,164.4,160.6,144.3,128.2,122.0,105.4,97.0,91.3,68.3,56.0,55.5,51.1,43.0,39.9,39.5,31.1,30.0,28.7,27.9,7.5.IR(neat,cm-1)2960,2925,2854,1744,1621,1461,1261,1095,1025,802.HRMS(ESI)[M+H]+Calcd for C22H27N2O4 383.1965,Found 383.1965.[α]D 25-180.0(c 0.5,CHCl3).The test data of the compound of the formula (6a) are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 8.96 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H) ), 6.42 (dd, J = 8.1, 2.3 Hz, 1H), 4.13 (dd, J = 11.7, 7.6 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.41 (d, J = 1.6 Hz, 1H), 3.37 (td, J = 12.0, 5.5 Hz, 1H), 2.63 (dd, J = 15.5, 1.8 Hz, 1H), 2.37 (dt, J = 15.3, 4.2 Hz, 1H), 2.27 ( Td, J = 14.2, 5.0 Hz, 1H), 2.01 - 1.92 (m, 2H), 1.89 (d, J = 15.5 Hz, 1H), 1.79 (dd, J = 12.2, 5.4 Hz, 1H), 1.34 (td , J = 13.2, 4.2 Hz, 1H), 0.98 (q, J = 7.3 Hz, 2H), 0.69 (t, J = 7.3 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 171.6, 168.3, 164.4, 160.6, 144.3, 128.2, 122.0, 105.4, 97.0, 91.3, 68.3, 56.0, 55.5, 51.1, 43.0, 39.9, 39.5, 31.1, 30.0, 28.7, 27.9, 7.5. IR (neat, cm -1 ) 2960, 2925, 2854,1744,1621,1461,1261,1095,1025,802.HRMS(ESI)[M+H] + Calcd for C 22 H 27 N 2 O 4 383.1965,Found 383.1965.[α] D 25 -180.0(c 0.5, CHCl 3 ).
实施例9Example 9
式(7a)化合物的合成Synthesis of the compound of formula (7a)
Figure PCTCN2017098979-appb-000022
Figure PCTCN2017098979-appb-000022
将式(6a)化合物(873mg,2.28mmol,1.0equiv.)溶于甲苯(23mL)中，室温下加入Lawesson’s试剂(1.02g,2.51mmol,1.1equiv.).将反应升至80℃回流30分钟。反应完毕，冷却至室温，向反应体系中加入饱和氯化钠溶液(50mL).体系用乙酸乙酯(3x 50mL)萃取，有 机相用饱和食盐水(3x 50mL)洗，无水硫酸钠干燥，过滤，减压除去溶剂后直接柱层析(石油醚:乙酸乙酯＝10:1)得到白色固体式(7a)化合物(609mg,67％)。The compound of the formula (6a) (873 mg, 2.28 mmol, 1.0 equiv.) was dissolved in toluene (23 mL). Lawesson's reagent (1.02 g, 2.51 mmol, 1.1 equiv.) was added at room temperature. The reaction was refluxed to 80 ° C for 30 minutes. . After the reaction was completed, it was cooled to room temperature, and a saturated sodium chloride solution (50 mL) was added to the reaction system. The system was extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated aqueous sodium chloride (3×50 mL), dried over anhydrous sodium sulfate. 609 mg, 67%).
式(7a)化合物的检测数据如下：1H NMR(500MHz,CDCl3)δ8.97(s,1H),7.08(d,J＝8.2Hz,1H),6.46(d,J＝2.2Hz,1H),6.43(dd,J＝8.2,2.3Hz,1H),4.60(dd,J＝13.1,7.9Hz,1H),3.79(s,3H),3.78(s,3H),3.70(td,J＝13.0,6.1Hz,1H),3.34(s,1H),3.10(dt,J＝15.3,3.1Hz,1H),2.72(dd,J＝15.7,1.7Hz,1H),2.52(td,J＝14.3,3.4Hz,1H),2.09(td,J＝12.7,8.0Hz,1H),2.01(dt,J＝12.5,3.0Hz,1H),1.93(dd,J＝12.5,5.9Hz,1H),1.80(d,J＝15.6Hz,1H),1.17(td,J＝13.8,1.8Hz,1H),1.06–1.01(m,1H),1.00–0.94(m,1H),0.70(t,J＝7.3Hz,3H).13C NMR(125MHz,CDCl3)δ200.5,168.2,163.6,160.8,144.2,127.6,122.0,105.5,97.2,91.5,70.7,56.0,55.6,51.2,49.6,41.3,40.4,39.0,30.2,29.5,27.5,7.3.IR(neat,cm-1)3353,2959,2924,2854,1620,1463,1261,1104,803.HRMS(ESI)[M+H]+Calcd for C22H27N2O3S 399.1737,Found399.1735.[α]D 25-44.8(c 0.5,CHCl3).The test data for the compound of the formula (7a) are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 8.97 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H) ), 6.43 (dd, J = 8.2, 2.3 Hz, 1H), 4.60 (dd, J = 13.1, 7.9 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.70 (td, J = 13.0, 6.1 Hz, 1H), 3.34 (s, 1H), 3.10 (dt, J = 15.3, 3.1 Hz, 1H), 2.72 (dd, J = 15.7, 1.7 Hz, 1H), 2.52 (td, J = 14.3) , 3.4 Hz, 1H), 2.09 (td, J = 12.7, 8.0 Hz, 1H), 2.01 (dt, J = 12.5, 3.0 Hz, 1H), 1.93 (dd, J = 12.5, 5.9 Hz, 1H), 1.80 (d, J = 15.6 Hz, 1H), 1.17 (td, J = 13.8, 1.8 Hz, 1H), 1.06 - 1.01 (m, 1H), 1.00 - 0.94 (m, 1H), 0.70 (t, J = 7.3) Hz,3H). 13 C NMR (125MHz, CDCl 3 ) δ 200.5,168.2,163.6,160.8,144.2,127.6,122.0,105.5,97.2,91.5,70.7,56.0,55.6,51.2,49.6,41.3,40.4,39.0, 30.2, 29.5, 27.5, 7.3. IR (neat, cm -1 ) 3353, 2959, 2924, 2854, 1620, 1463, 1261, 1104, 803. HRMS (ESI) [M+H] + Calcd for C 22 H 27 N 2 O 3 S 399.1737, Found 399.1735. [α] D 25 -44.8 (c 0.5, CHCl 3 ).
实施例10Example 10
式(8a)化合物的合成Synthesis of the compound of formula (8a)
Figure PCTCN2017098979-appb-000023
Figure PCTCN2017098979-appb-000023
将式(7a)化合物(589mg,1.48mmol,1.0equiv.)溶于甲苯(60mL)中，室温下加入N,N-二异丙基乙胺(955mg,7.39mmol,5.0equiv.).氮气氛围下加入新制备的对甲基苯亚黄酰氯(645mg,3.69mmol,2.5equiv.).将反应升至110℃回流10分钟。反应完毕，冷却至室温，减压除去溶剂后直接柱层析(石油醚:乙酸乙酯＝10:1)得到淡黄色固体式(8a)化合物(383mg,65％)。The compound of the formula (7a) (589 mg, 1.48 mmol, 1.0 equiv.) was dissolved in toluene (60 mL), and N,N-diisopropylethylamine (955 mg, 7.39 mmol, 5.0 equiv.) was added at room temperature. The newly prepared p-tolueneoxyl chloride (645 mg, 3.69 mmol, 2.5 equiv.) was added. The reaction was allowed to reflux to 110 ° C for 10 minutes. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated, evaporated, mjjjjjjjj
式(8a)化合物的检测数据如下：1H NMR(500MHz,CDCl3)δ8.99(s,1H),7.14(d,J＝8.0Hz,1H),6.51–6.39(m,3H),6.14(d,J＝9.6Hz,1H),4.88(dd,J＝12.6,7.1Hz,1H),3.85(s,1H),3.80(s,3H),3.77(s,3H),3.67(td,J＝12.5,5.1Hz,1H),2.58(dd,J＝15.6,1.7Hz,1H),2.04–1.99(m,2H),1.96(dd,J＝12.3,5.3Hz,1H),1.12(dq,J＝14.8,7.4Hz,1H),1.01(dq,J＝14.4,7.3Hz,1H),0.72(t,J＝7.4Hz,3H).13C NMR(125MHz,CDCl3)δ186.3,168.2,165.5,160.8,144.0,136.7,129.4,127.4,121.7,105.7,97.3,90.5,68.0,55.5,55.4,51.2,49.5,42.8,40.4,27.2,24.9,7.1.IR(neat,cm-1)2923,2854,1680,1616,1456,1234,1078,806.HRMS(ESI)[M+H]+Calcd for  C22H25N2O3S 397.1580,Found 397.1579.[α]D 25-3.2(c 0.5,CHCl3).The test data for the compound of the formula (8a) are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 8.99 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.51 - 6.39 (m, 3H), 6.14 (d, J = 9.6 Hz, 1H), 4.88 (dd, J = 12.6, 7.1 Hz, 1H), 3.85 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.67 (td, J=12.5, 5.1 Hz, 1H), 2.58 (dd, J=15.6, 1.7 Hz, 1H), 2.04–1.99 (m, 2H), 1.96 (dd, J=12.3, 5.3 Hz, 1H), 1.12 (dq) , J = 14.8, 7.4 Hz, 1H), 1.01 (dq, J = 14.4, 7.3 Hz, 1H), 0.72 (t, J = 7.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 186.3, 168.2, 165.5, 160.8, 144.0, 136.7, 129.4, 127.4, 121.7, 105.7, 97.3, 90.5, 68.0, 55.5, 55.4, 51.2, 49.5, 42.8, 40.4, 27.2, 24.9, 7.1. IR (neat, cm -1 ) 2923, 2854,1680,1616,1456,1234,1078,806.HRMS(ESI)[M+H] + Calcd for C 22 H 25 N 2 O 3 S 397.1580,Found 397.1579.[α] D 25 -3.2(c 0.5 , CHCl 3 ).
实施例11Example 11
式(12a)所示(-)-16-methoxytabersonine的合成Synthesis of (-)-16-methoxytabersonine represented by formula (12a)
Figure PCTCN2017098979-appb-000024
Figure PCTCN2017098979-appb-000024
将式(8a)化合物(383mg,0.97mmol,1.0equiv.)溶于二氯甲烷(10mL)中，0℃下加入三甲氧基四氟硼酸盐(429mg,2.90mmol,3.0equiv.).在0℃下反应2小时，向反应体系加入甲醇(10mL),搅拌15分钟后,加入硼氢化钠(366mg,9.67mmol,10.0equiv.).在0℃下反应30分钟。反应液用饱和碳酸氢钠溶液(20mL)淬灭.二氯甲烷(3x 50mL)萃取.合并有机相无水硫酸钠干燥，过滤，减压除去溶剂后直接柱层析(石油醚:乙酸乙酯＝10:1)得到白色固体式(12a)(-)-16-methoxytabersonine(184mg,52％)。The compound of the formula (8a) (383 mg, 0.97 mmol, 1.0 equiv.) was dissolved in dichloromethane (10 mL), and trimethoxytetrafluoroborate (429 mg, 2.90 mmol, 3.0 equiv.) was added at 0 ° C. After reacting at 0 ° C for 2 hours, methanol (10 mL) was added to the reaction mixture, and after stirring for 15 minutes, sodium borohydride (366 mg, 9.67 mmol, 10.0 equiv.) was added. The reaction was carried out at 0 ° C for 30 minutes. The reaction mixture was quenched with EtOAc EtOAc (EtOAc (EtOAc) = 10:1) gave (12a) (-)-16-methoxytabersonine (184 mg, 52%) as a white solid.
式(12a)(-)-16-methoxytabersonine的检测数据如下:1H NMR(500MHz,CDCl3)δ8.96(s,1H),7.10(d,J＝8.0Hz,1H),6.41(d,J＝2.1Hz,1H),6.39(dd,J＝8.1,2.2Hz,1H),5.78(ddd,J＝9.9,4.7,1.3Hz,1H),5.70(d,J＝9.9Hz,1H),3.78(s,3H),3.77(s,3H),3.45(dd,J＝15.0,3.3Hz,1H),3.17(d,J＝15.8Hz,1H),3.03(t,J＝7Hz,1H),2.73–2.65(m,1H),2.62(s,1H),2.54(d,J＝15.1Hz,1H),2.42(d,J＝15.1Hz,1H),2.05(td,J＝11,6.5Hz,1H),1.77(dd,J＝11.5,4.3Hz,1H),1.01(dq,J＝14.9,7.5Hz,1H),0.85(dq,J＝15.0,7.5Hz,1H),0.64(t,J＝7.5Hz,3H).13C NMR(125MHz,CDCl3)δ169.0,167.2,160.0,144.4,133.1,130.5,124.9,121.8,105.0,96.7,92.4,70.2,55.5,54.5,51.0,50.9,50.6,44.6,41.4,28.4,26.9,7.5.IR(neat,cm-1)3370,2923,2853,1676,1615,1457,1256,1152,798.HRMS(ESI)[M+H]+Calcd for C22H27N2O3 367.2016,Found367.2012.[α]D 21-214.8(c 0.21,CHCl3).The test data of the formula (12a) (-)-16-methoxytabersonine are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 8.96 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 6.39 (dd, J=8.1, 2.2 Hz, 1H), 5.78 (ddd, J=9.9, 4.7, 1.3 Hz, 1H), 5.70 (d, J=9.9 Hz, 1H), 3.78(s,3H),3.77(s,3H), 3.45(dd,J=15.0,3.3Hz,1H), 3.17(d,J=15.8Hz,1H),3.03(t,J=7Hz,1H) , 2.73–2.65(m,1H), 2.62(s,1H),2.54(d,J=15.1Hz,1H),2.42(d,J=15.1Hz,1H),2.05(td,J=11,6.5 Hz, 1H), 1.77 (dd, J = 11.5, 4.3 Hz, 1H), 1.01 (dq, J = 14.9, 7.5 Hz, 1H), 0.85 (dq, J = 15.0, 7.5 Hz, 1H), 0.64 (t , J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 169.0, 167.2, 160.0, 144.4, 133.1, 130.5, 124.9, 121.8, 105.0, 96.7, 92.4, 70.2, 55.5, 54.5, 51.0, 50.9, 50.6, 44.6, 41.4, 28.4, 26.9, 7.5. IR (neat, cm -1 ) 3370, 2923, 2853, 1676, 1615 , 1457, 1256, 1152, 798. HRMS (ESI) [M+H] + Calcd for C 22 H 27 N 2 O 3 367.2016, Found367.2012. [α] D 21 -214.8 (c 0.21, CHCl 3).
实施例12Example 12
式(10a)所示(-)-Aspidospermidine的合成 Synthesis of (-)-Aspidospermidine represented by formula (10a)
Figure PCTCN2017098979-appb-000025
Figure PCTCN2017098979-appb-000025
将式(4b)化合物(35.4mg,0.066mmol,1.0equiv.)溶于甲醇(6.6mL)中,依次加入三乙胺(33.4mg,0.33mmol,5.00equiv.)和Pd/C(10wt％,14mg,0.0132mmol,0.20equiv.)。反应瓶用氢气置换后在氢气氛围(氢气球)下搅拌8小时,过滤，乙酸乙酯(3x 50mL)洗涤滤饼。减压除掉溶剂得到白色固体(无需柱层析分离纯化)。The compound of the formula (4b) (35.4 mg, 0.066 mmol, 1.0 equiv.) was dissolved in methanol (6.6 mL), followed by triethylamine (33.4 mg, 0.33 mmol, 5.00 equiv.) and Pd/C (10 wt%, 14 mg, 0.0132 mmol, 0.20 equiv.). The reaction flask was replaced with hydrogen and stirred under a hydrogen atmosphere (hydrogen balloon) for 8 hours, filtered, and ethyl acetate (3×50 mL) washed. The solvent was removed under reduced pressure to give a white solid (purified by column chromatography).
将上述得到的白色固体溶于溶于四氢呋喃(1mL)中，–78℃下分三批等量加入四氢铝锂(25mg,0.66mmol,10.0equiv.)反应升至70℃回流13小时。反应完毕，冷却至室温，向反应体系中分别用水(250μL),15％氢氧化钠溶液(250μL)and水(750μL).搅拌30分钟后过滤除掉固体不容物。减压除去溶剂后直接柱层析(石油醚:乙酸乙酯:三乙胺＝100:10:1)得到白色固体式(10a)(-)-Aspidospermidine(7.7mg,41％yield for two steps)。The white solid obtained above was dissolved in tetrahydrofuran (1 mL), and a mixture of three portions of lithium aluminum hydride (25 mg, 0.66 mmol, 10.0 equiv.) was added in three portions at -78 ° C, and the mixture was refluxed at 70 ° C for 13 hours. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was stirred with water (250 μL), 15% sodium hydroxide solution (250 μL) and water (750 μL) for 30 minutes, and then filtered to remove solid contents. The solvent was removed under reduced pressure and purified by column chromatography (ethyl ether: ethyl acetate: triethylamine = 100:10:1) to give white solid (10a) (-)-Aspidospermidine (7.7 mg, 41% yield for two steps) .
式(10a)(-)-Aspidospermidine的检测数据如下:1H NMR(400MHz,CDCl3)δ7.08(d,J＝7.4Hz,1H),7.01(td,J＝7.6,1.2Hz,1H),6.72(td,J＝7.4,0.9Hz,1H),6.62(d,J＝7.7Hz,1H),3.51(dd,J＝11.0,6.2Hz,1H),3.12(dd,J＝10.1,7.5Hz,1H),3.05(d,J＝10.8Hz,1H),2.36–2.17(m,3H),2.03–1.88(m,2H),1.82–1.68(m,1H),1.67–1.59(m,2H),1.54–1.33(m,4H),1.12(td,J＝27.0,13.5Hz,1H),1.05(dt,J＝13.5,3.0Hz,1H),0.93–0.82(m,1H),0.64(t,J＝7.5Hz,3H).13C NMR(100MHz,CDCl3)δ149.4,135.6,127.0,122.7,118.9,110.2,71.2,65.6,53.8,53.3,52.9,38.8,35.6,34.4,29.9,28.0,23.0,21.7,6.7.IR(neat,cm-1)2931,2778,1606,1480,1462,1256,1178,1008.HRMS(EI)[M]+Calcd for C19H26N2 282.2096,Found 282.2099.[α]D 25-20.8(c0.5,EtOH)..The test data of the formula (10a) (-)-Aspidospermidine are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (d, J = 7.4 Hz, 1H), 7.01 (td, J = 7.6, 1.2 Hz, 1H) , 6.72 (td, J = 7.4, 0.9 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 3.51 (dd, J = 11.0, 6.2 Hz, 1H), 3.12 (dd, J = 10.1, 7.5 Hz, 1H), 3.05 (d, J = 10.8 Hz, 1H), 2.36 - 2.17 (m, 3H), 2.03 - 1.88 (m, 2H), 1.82 - 1.68 (m, 1H), 1.67 - 1.59 (m, 2H), 1.54–1.33 (m, 4H), 1.12 (td, J=27.0, 13.5 Hz, 1H), 1.05 (dt, J = 13.5, 3.0 Hz, 1H), 0.93–0.82 (m, 1H), 0.64 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 149.4, 135.6, 127.0, 122.7, 118.9, 110.2, 71.2, 65.6, 53.8, 53.3, 52.9, 38.8, 35.6, 34.4, 29.9, 28.0, 23.0, 21.7, 6.7. IR (neat, cm -1 ) 2931, 2778, 1606, 1480, 1462, 1256, 1178, 1008. HRMS (EI) [M] + Calcd for C 19 H 26 N 2 282.2096, Found 282.2099.[α] D 25 -20.8(c0.5,EtOH)..
实施例13Example 13
式(11a)所示(+)-N-Acetylaspidospermidine的合成 Synthesis of (+)-N-Acetylaspidospermidine represented by formula (11a)
Figure PCTCN2017098979-appb-000026
Figure PCTCN2017098979-appb-000026
将式(10a)(-)-aspidospermidine(36.9mg,0.13mmol,1.0equiv.)溶于吡啶(0.5mL)中，室温下加入乙酸酐(0.5mL).室温下搅拌3小时.将反应液置于0℃下,用氨水(1mL)淬灭反应，体系用二氯甲烷(3x 10mL)萃取.合并有机相无水硫酸钠干燥，过滤，减压除去溶剂后直接柱层析(石油醚:乙酸乙酯:三乙胺＝100:50:2)得到无色液体式(11a)(+)-N-Acetylaspidospermidine(36.9mg,88％)。The formula (10a) (-)-aspidospermidine (36.9 mg, 0.13 mmol, 1.0 equiv.) was dissolved in pyridine (0.5 mL), and acetic anhydride (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with aqueous EtOAc (1 mL). EtOAc (EtOAc m. Ethyl ester: triethylamine = 100:50:2) (#a)-N-Acetylaspidospermidine (36.9 mg, 88%) was obtained as a colorless liquid.
式(11a)(+)-N-Acetylaspidospermidine的检测数据如下:1H NMR(500MHz,CDCl3)δ8.12(d,J＝8.0Hz,1H),7.18(dd,J＝14.2,7.4Hz,2H),7.03(t,J＝7.5Hz,1H),4.06(dd,J＝11.2,6.2Hz,1H),3.13(td,J＝9.1,2.7Hz,1H),3.06(d,J＝10.8Hz,1H),2.30(s,1H),2.26(s,3H),2.15–2.06(m,1H),2.04–1.95(m,2H),1.92–1.86(m,1H),1.78–1.70(m,2H),1.65(d,J＝14.1Hz,1H),1.57–1.36(m,4H),1.15–1.09(m,2H),0.92–0.86(m,1H),0.64(t,J＝7.5Hz,3H).13C NMR(125MHz,CDCl3)δ168.4,140.6,138.5,127.4,124.2,122.3,118.2,70.7,68.2,53.8,52.8,52.6,39.7,35.5,34.0,30.0,25.7,23.2,23.0,21.5,6.8.IR(neat,cm-1)2963,1659,`1478,1399,1258,1011.HRMS(EI)[M]+Calcd for C21H28N2O 324.2202,Found 324.2198.[α]D 25+14.6(c 0.5,CHCl3).The test data of the formula (11a)(+)-N-Acetylaspidospermidine are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 8.12 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 14.2, 7.4 Hz, 2H), 7.03 (t, J = 7.5 Hz, 1H), 4.06 (dd, J = 11.2, 6.2 Hz, 1H), 3.13 (td, J = 9.1, 2.7 Hz, 1H), 3.06 (d, J = 10.8) Hz, 1H), 2.30 (s, 1H), 2.26 (s, 3H), 2.15–2.06 (m, 1H), 2.04–1.95 (m, 2H), 1.92–1.86 (m, 1H), 1.78–1.70 ( m, 2H), 1.65 (d, J = 14.1 Hz, 1H), 1.57 - 1.36 (m, 4H), 1.15 - 1.09 (m, 2H), 0.92 - 0.86 (m, 1H), 0.64 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 168.4, 140.6, 138.5, 127.4, 124.2, 122.3, 118.2, 70.7, 68.2, 53.8, 52.8, 52.6, 39.7, 35.5, 34.0, 30.0, 25.7, 23.2 , 23.0, 21.5, 6.8. IR (neat, cm -1 ) 2963, 1659, `1478, 1399, 1258, 1011. HRMS (EI) [M] + Calcd for C 21 H 28 N 2 O 324.2202, Found 324.2198. [α] D 25 +14.6 (c 0.5, CHCl 3 ).
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。 The protection of the present invention is not limited to the above embodiment. Variations and advantages that may be conceived by those skilled in the art are intended to be included within the scope of the invention and the scope of the appended claims.

Claims (22)

  1. 一种不对称合成白坚木属生物碱的方法，其特征在于，所述方法包括以下步骤：A method for asymmetrically synthesizing albino alkaloids, characterized in that the method comprises the following steps:
    (一)式(1)化合物的合成(a) Synthesis of the compound of formula (1)
    步骤(l)：将式(1a)化合物和式(1b)化合物(或式(ent-1b)化合物)溶于有机溶剂中，进行加成反应，得到式(1c)化合物(或式(ent-1c)化合物)；Step (l): dissolving the compound of the formula (1a) and the compound of the formula (1b) (or the compound of the formula (ent-1b)) in an organic solvent to carry out an addition reaction to obtain a compound of the formula (1c) (or formula (ent- 1c) compound);
    步骤(m)式(1d)化合物或式(ent-1d)化合物的合成Step (m) Synthesis of a compound of formula (1d) or a compound of formula (ent-1d)
    (m-1)将式(1c)化合物或式(ent-1c)化合物溶于三氟乙酸中，进行取代反应，得到褐色油状液体5-溴-7-乙基-8-氧代-2,3,3a,4,7,7a-六氢-1H-4,7-(环氧甲烷基)吲哚-2-羧酸；(m-1) A compound of the formula (1c) or a compound of the formula (ent-1c) is dissolved in trifluoroacetic acid to carry out a substitution reaction to obtain a 5-bromo-7-ethyl-8-oxo-2 liquid as a brown oil. 3,3a,4,7,7a-hexahydro-1H-4,7-(epoxymethylalkyl)indole-2-carboxylic acid;
    (m-2)将褐色油状液体5-溴-7-乙基-8-氧代-2,3,3a,4,7,7a-六氢-1H-4,7-(环氧甲烷基)吲哚-2-羧酸溶于混合溶剂中，加入碳酸氢钠固体和氯甲酸苄酯，进行取代反应，得到式(1d)化合物或式(ent-1d)化合物；(m-2) a brown oily liquid 5-bromo-7-ethyl-8-oxo-2,3,3a,4,7,7a-hexahydro-1H-4,7-(epoxymethylalkyl) The hydrazine-2-carboxylic acid is dissolved in a mixed solvent, and a sodium hydrogencarbonate solid and benzyl chloroformate are added to carry out a substitution reaction to obtain a compound of the formula (1d) or a compound of the formula (ent-1d);
    步骤(n)式(1)化合物或式(ent-1)化合物的合成Step (n) Synthesis of a compound of formula (1) or a compound of formula (ent-1)
    (n-1)将式(1d)化合物(或式(ent-1d)化合物)、醋酸碘苯和碘溶于有机溶剂中，进行消去反应，得到亚胺阳离子中间体化合物；(n-1) dissolving a compound of the formula (1d) (or a compound of the formula (ent-1d), iodobenzene acetate and iodine in an organic solvent to carry out an elimination reaction to obtain an imine cation intermediate compound;
    (n-2)将亚胺阳离子中间体化合物和三乙基硅氢进行加成反应，得到式(1)化合物(或式(ent-1)化合物)；(n-2) an addition reaction of an imine cationic intermediate compound and triethylsilyl hydrogen to obtain a compound of the formula (1) (or a compound of the formula (ent-1));
    (二)白坚木属生物碱的合成(2) Synthesis of alkaloids from the genus Baijianmu
    步骤(a)式(2)化合物的合成：Step (a) Synthesis of the compound of formula (2):
    (a-1)将式(1)化合物将溶于有机溶剂中，加入二异丁基氢化铝，进行还原反应，得到无色油状液体(3aS，4S，7S，7aR)-5-溴-7-乙基-4-羟基-7-((E)-3-甲氧基-3-氧代丙-1-烯基)-2,3，3a，4，7，7a-六氢-1H-吲哚-1-羧酸苄酯；(a-1) The compound of the formula (1) is dissolved in an organic solvent, and diisobutylaluminum hydride is added to carry out a reduction reaction to obtain a colorless oily liquid (3aS, 4S, 7S, 7aR)-5-bromo-7. -ethyl-4-hydroxy-7-((E)-3-methoxy-3-oxoprop-1-enyl)-2,3,3a,4,7,7a-hexahydro-1H- Benzyl-1-carboxylate;
    (a-2)将步骤(a-1)得到的无色油状液体(3aS，4S，7S，7aR)-5-溴-7-乙基-4-羟基-7-((E)-3-甲氧基-3-氧代丙-1-烯基)-2,3，3a，4，7，7a-六氢-1H-吲哚-1-羧酸苄酯溶于有机溶剂中，加入Wittig试剂Ph3P＝CHCO2R1，进行取代反应，得到式(2)化合物；(a-2) Colorless oily liquid (3aS, 4S, 7S, 7aR)-5-bromo-7-ethyl-4-hydroxy-7-((E)-3- obtained in the step (a-1) Benzyl-3-oxoprop-1-enyl)-2,3,3a,4,7,7a-hexahydro-1H-indole-1-carboxylic acid benzyl ester is dissolved in an organic solvent and added to Wittig The reagent Ph 3 P=CHCO 2 R 1 is subjected to a substitution reaction to obtain a compound of the formula (2);
    步骤(b)：将式(2)化合物溶于有机溶剂中，加入戴斯-马丁氧化剂，进行氧化反应，得到式(3)化合物；Step (b): dissolving the compound of the formula (2) in an organic solvent, adding a Dess-Martin oxidizing agent, and performing an oxidation reaction to obtain a compound of the formula (3);
    步骤(c)式(4)化合物的合成：Step (c) Synthesis of the compound of formula (4):
    (c-1)将式(3)化合物和芳香肼溶于有机溶剂中，进行取代反应，得到芳腙中间体；(c-1) dissolving the compound of the formula (3) and the aromatic hydrazine in an organic solvent to carry out a substitution reaction to obtain an aryl hydrazine intermediate;
    (c-2)将芳腙中间体溶于有机溶剂中，加入三氟乙酸，进行重排反应，得到式(4)化合物；制备的式(4)化合物通过两种方法制备目标化合物：(c-2) dissolving the aryl hydrazine intermediate in an organic solvent, adding trifluoroacetic acid, and performing a rearrangement reaction to obtain a compound of the formula (4); and preparing the compound of the formula (4) by two methods:
    方法一：method one:
    步骤(d)：将式(4)化合物溶于有机溶剂中，加入三乙胺和四三苯基膦钯，进行取代反应， 得到得到式(5)化合物；Step (d): dissolving the compound of the formula (4) in an organic solvent, adding triethylamine and tetrakistriphenylphosphine palladium, and performing a substitution reaction. Obtaining a compound of formula (5);
    步骤(e)：将式(5)化合物溶于有机溶剂中，依次加入三乙胺和钯/碳(Pd/C)，进行还原反应，得到式(6)化合物；Step (e): dissolving the compound of the formula (5) in an organic solvent, and sequentially adding triethylamine and palladium/carbon (Pd/C) to carry out a reduction reaction to obtain a compound of the formula (6);
    步骤(f)：将式(6)化合物溶于有机溶剂中，加入Lawesson’s试剂，进行取代反应，得到式(7)化合物；Step (f): dissolving the compound of the formula (6) in an organic solvent, adding Lawesson's reagent, and performing a substitution reaction to obtain a compound of the formula (7);
    步骤(g)：将式(7)化合物溶于有机溶剂中，加入对甲基苯亚黄酰氯胺和二异丙基乙胺，进行还原反应，得到式(8)化合物；Step (g): the compound of the formula (7) is dissolved in an organic solvent, and p-methylbenzene-xylyl chloramine and diisopropylethylamine are added to carry out a reduction reaction to obtain a compound of the formula (8);
    步骤(h)：式(12)化合物的合成Step (h): Synthesis of a compound of formula (12)
    (h-1)将式(8)化合物溶于有机溶剂中，加入三甲氧基四氟硼酸鎓盐，进行取代反应，得到硫甲基化合物中间体；(h-1) dissolving the compound of the formula (8) in an organic solvent, adding a ruthenium trimethoxytetrafluoroborate salt, and performing a substitution reaction to obtain a thiomethyl compound intermediate;
    (h-2)然后加入硼氢化钠，进行还原反应，得到目标化合物式(12)化合物白坚木属生物碱；方法二：(h-2) Then, sodium borohydride is added to carry out a reduction reaction to obtain a compound of the formula (12), which is a compound of the formula (12);
    步骤(i)：将式(4)化合物溶于有机溶剂中，加入三乙胺和钯/碳(Pd/C)，进行还原反应，得到式(9)化合物；Step (i): dissolving the compound of the formula (4) in an organic solvent, adding triethylamine and palladium/carbon (Pd/C) to carry out a reduction reaction to obtain a compound of the formula (9);
    步骤(j)：将式(9)化合物溶于有机溶剂中，依次加入四氢铝锂，进行还原反应，得到式(10)化合物白坚木属生物碱；Step (j): dissolving the compound of the formula (9) in an organic solvent, sequentially adding lithium tetrahydrogenate, and performing a reduction reaction to obtain a compound of the formula (10);
    步骤(k)：在有机溶剂中，将式(10)化合物加入碱和乙酰化试剂，进行取代反应，分别得到目标化合物式(11)化合物白坚木属生物碱；Step (k): adding a compound of the formula (10) to a base and an acetylating reagent in an organic solvent to carry out a substitution reaction to obtain a compound of the formula (11), a compound of the formula A.
    反应过程如路线(1)～(2)所示；The reaction process is as shown in routes (1) to (2);
    Figure PCTCN2017098979-appb-100001
    Figure PCTCN2017098979-appb-100001
    Figure PCTCN2017098979-appb-100002
    Figure PCTCN2017098979-appb-100002
    其中，所述芳香肼的结构式为
    Figure PCTCN2017098979-appb-100003
    Wherein the structural formula of the aromatic oxime is
    Figure PCTCN2017098979-appb-100003
    其中，所述芳腙中间体的结构式为：
    Figure PCTCN2017098979-appb-100004
    Wherein, the structural formula of the aryl hydrazine intermediate is:
    Figure PCTCN2017098979-appb-100004
    其中，R1选自C1-C20烷基；R2选自氢、C1-C20烷基、三氟甲基、C1-C20烷氧基、卤素。 Wherein R 1 is selected from C1-C20 alkyl; R 2 is selected from hydrogen, C1-C20 alkyl, trifluoromethyl, C1-C20 alkoxy, halogen.
  2. 如权利要求1所述的方法，其特征在于，如权利要求1所述的方法，其特征在于，步骤(l)中，所述加成反应的温度为90℃～110℃；和/或，所述有机溶剂选自甲苯、苯、二氯甲烷中的一种或多种；和/或，式(1a)化合物和式(1b)化合物(或式(ent-1b)化合物)的摩尔比为1:(1～2)。The method according to claim 1, wherein in the step (1), the temperature of the addition reaction is from 90 ° C to 110 ° C; and/or The organic solvent is selected from one or more of toluene, benzene, dichloromethane; and/or the molar ratio of the compound of the formula (1a) to the compound of the formula (1b) (or the compound of the formula (ent-1b)) is 1: (1 ~ 2).
  3. 如权利要求1所述的方法，其特征在于，步骤(m-1)中，所述取代反应的温度为0～40℃；和/或，所述式(1c)化合物或式(ent-1c)化合物和三氟乙酸的摩尔比为1:(5～15)。The method according to claim 1, wherein in the step (m-1), the temperature of the substitution reaction is 0 to 40 ° C; and/or the compound of the formula (1c) or the formula (ent-1c) The molar ratio of the compound to trifluoroacetic acid is 1: (5-15).
  4. 如权利要求1所述的方法，其特征在于，步骤(m-2)中，所述取代反应的温度为0～40℃；和/或，所述混合溶剂选自四氢呋喃和水的混合溶剂、丙酮和水的混合溶剂；和/或，所述褐色油状液体，氯甲酸苄酯和碳酸氢钠的摩尔比为1:5:(5～20)。The method according to claim 1, wherein in the step (m-2), the temperature of the substitution reaction is 0 to 40 ° C; and/or the mixed solvent is selected from the group consisting of a mixed solvent of tetrahydrofuran and water, a mixed solvent of acetone and water; and/or a brown oily liquid, a molar ratio of benzyl chloroformate to sodium hydrogencarbonate of 1:5: (5 to 20).
  5. 如权利要求1所述的方法，其特征在于，步骤(n-1)中，所述消去反应的温度为25℃～40℃；和/或，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷中的一种或多种。The method according to claim 1, wherein in the step (n-1), the temperature of the elimination reaction is from 25 ° C to 40 ° C; and/or the organic solvent is selected from the group consisting of dichloromethane, 1, One or more of 2-dichloroethane.
  6. 如权利要求1所述的方法，其特征在于，步骤(n-2)中，所述加成反应的温度为0～40℃；和/或，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷中的一种或多种；和/或，步骤(n)中，式(1d)化合物(或式(ent-1d)化合物)，醋酸碘苯，碘和三乙基硅氢的摩尔比为1:2:(0.1～0.5):5。The method according to claim 1, wherein in the step (n-2), the temperature of the addition reaction is 0 to 40 ° C; and/or the organic solvent is selected from the group consisting of dichloromethane and 1, One or more of 2-dichloroethane; and/or, in step (n), a compound of formula (1d) (or a compound of formula (ent-1d)), iodobenzene acetate, iodine and triethylsilane The molar ratio of hydrogen is 1:2: (0.1 to 0.5): 5.
  7. 如权利要求1所述的方法，其特征在于，步骤(a-1)中，所述有机溶剂选自甲苯、四氢呋喃、二氯甲烷、1,2-二氯乙烷；和/或，所述式(1)化合物与二异丁基氢化铝的摩尔比为1:(1.2～2)。The method according to claim 1, wherein in the step (a-1), the organic solvent is selected from the group consisting of toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane; and/or The molar ratio of the compound of the formula (1) to diisobutylaluminum hydride is 1: (1.2 to 2).
  8. 如权利要求1所述的方法，其特征在于，步骤(a-2)中，所述取代反应的温度为25℃～110℃和/或，所述有机溶剂选自甲苯、四氢呋喃、二氯甲烷、1,2-二氯乙烷；所述无色油状液体与Wittig试剂Ph3P＝CHCO2R1的摩尔比为1:(1.5～2)。The method according to claim 1, wherein in the step (a-2), the temperature of the substitution reaction is from 25 ° C to 110 ° C and/or the organic solvent is selected from the group consisting of toluene, tetrahydrofuran, and dichloromethane. 1,2-dichloroethane; the molar ratio of the colorless oily liquid to the Wittig reagent Ph 3 P=CHCO 2 R 1 is 1: (1.5 to 2).
  9. 如权利要求1所述的方法，其特征在于，步骤(b)中，所述氧化反应的温度为0℃～25℃；和/或，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、四氢呋喃、1,4-二氧六环；和/或，所述式(2)化合物和戴斯-马丁氧化剂的摩尔比为1:(1.2～5)。The method according to claim 1, wherein in the step (b), the temperature of the oxidation reaction is from 0 ° C to 25 ° C; and/or the organic solvent is selected from the group consisting of dichloromethane, 1,2- Dichloroethane, tetrahydrofuran, 1,4-dioxane; and/or the molar ratio of the compound of the formula (2) to the Dess-Martin periodinator is 1: (1.2 to 5).
  10. 如权利要求1所述的方法，其特征在于，步骤(c-1)中，所述取代反应的温度为25℃～110℃；和/或，所述第一有机溶剂选自乙醇、苯、甲苯、二甲苯、1,2-二氯乙烷；和/或，所述式(3)化合物与芳香肼的摩尔比为1:(2～4)。The method according to claim 1, wherein in the step (c-1), the temperature of the substitution reaction is from 25 ° C to 110 ° C; and/or the first organic solvent is selected from the group consisting of ethanol and benzene. Toluene, xylene, 1,2-dichloroethane; and/or the molar ratio of the compound of the formula (3) to the aromatic hydrazine is 1: (2 to 4).
  11. 如权利要求1所述的方法，其特征在于，步骤(c-2)中，所述重排反应的温度为40℃～120℃；和/或，所述有机溶剂选自1,2-二氯乙烷、乙酸、乙醇、叔丁醇、1,4-二氧六环；和/或，所述芳香腙与三氟乙酸的摩尔比为1:(10～50)。The method according to claim 1, wherein in the step (c-2), the temperature of the rearrangement reaction is from 40 ° C to 120 ° C; and/or the organic solvent is selected from the group consisting of 1, 2 - 2 Ethyl chloride, acetic acid, ethanol, tert-butanol, 1,4-dioxane; and/or the molar ratio of the aromatic hydrazine to trifluoroacetic acid is 1: (10 to 50).
  12. 如权利要求1所述的方法，其特征在于，步骤(d)中，所述取代反应的温度为80℃～100℃；和/或，所述有机溶剂选自甲醇、甲醇/四氢呋喃、乙醇/四氢呋喃、甲醇/N,N-二甲基甲酰 胺、N,N-二甲基甲酰胺；和/或，所述式(4)化合物，三乙胺和四三苯基膦钯的摩尔比为1:3:(0.05～0.2)。The method according to claim 1, wherein in the step (d), the temperature of the substitution reaction is from 80 ° C to 100 ° C; and/or the organic solvent is selected from the group consisting of methanol, methanol/tetrahydrofuran, and ethanol/ Tetrahydrofuran, methanol/N,N-dimethylformyl An amine, N,N-dimethylformamide; and/or a molar ratio of the compound of the formula (4), triethylamine and tetrakistriphenylphosphine palladium of 1:3: (0.05 to 0.2).
  13. 如权利要求1所述的方法，其特征在于，步骤(e)中，所述还原反应的温度为0℃～50℃；和/或，所述有机溶剂选自甲醇、乙酸乙酯、乙醇、四氢呋喃；和/或，所述式(5)化合物、三乙胺和钯/碳的摩尔比为1:5:(0.1～0.5)。The method according to claim 1, wherein in the step (e), the temperature of the reduction reaction is from 0 ° C to 50 ° C; and/or the organic solvent is selected from the group consisting of methanol, ethyl acetate, ethanol, Tetrahydrofuran; and/or the molar ratio of the compound of the formula (5), triethylamine and palladium/carbon is 1:5: (0.1 to 0.5).
  14. 如权利要求1所述的方法，其特征在于，步骤(f)中，所述取代反应的温度为80℃～100℃；和/或，所述有机溶剂选自苯、甲苯、二甲苯、四氢呋喃；和/或，所述式(6)化合物和Lawesson’s试剂的摩尔比为1:(1～1.2)。The method according to claim 1, wherein in the step (f), the temperature of the substitution reaction is from 80 ° C to 100 ° C; and/or the organic solvent is selected from the group consisting of benzene, toluene, xylene, and tetrahydrofuran. And/or, the molar ratio of the compound of the formula (6) to Lawesson's reagent is 1: (1 to 1.2).
  15. 如权利要求1所述的方法，其特征在于，步骤(g)中，所述还原反应的温度为40℃～110℃；和/或，所述有机溶剂选自二氯甲烷、甲苯、1，2-二氯乙烷、苯；和/或，所述式(7)化合物、二异丙基乙胺和对甲基苯亚黄酰氯胺的摩尔比为1:5:(1～2.5)。The method according to claim 1, wherein in the step (g), the temperature of the reduction reaction is from 40 ° C to 110 ° C; and/or the organic solvent is selected from the group consisting of dichloromethane, toluene, and 1, 2-Dichloroethane, benzene; and/or the molar ratio of the compound of the formula (7), diisopropylethylamine and p-methylbenzene-xamoyl chloramine is 1:5: (1 to 2.5).
  16. 如权利要求1所述的方法，其特征在于，步骤(h-1)中，所述取代反应的温度为–10℃～25℃；和/或，所述取代反应中，有机溶剂选自二氯甲烷、四氢呋喃、1,2-二氯乙烷；和/或，所述式(8)化合物与三甲氧基四氟硼酸鎓盐的摩尔比为1:(1～3)。The method according to claim 1, wherein in the step (h-1), the temperature of the substitution reaction is from -10 ° C to 25 ° C; and/or, in the substitution reaction, the organic solvent is selected from the group consisting of Methyl chloride, tetrahydrofuran, 1,2-dichloroethane; and/or the molar ratio of the compound of the formula (8) to the cerium trimethoxytetrafluoroborate is 1: (1-3).
  17. 如权利要求1所述的方法，其特征在于，步骤(h-2)中，所述还原反应的温度为0℃～25℃；和/或，所述有机溶剂选自甲醇、二氯甲烷、四氢呋喃、1,2-二氯乙烷；和/或，所述式(8)化合物与硼氢化钠的摩尔比为1:(5～20)。The method according to claim 1, wherein in the step (h-2), the temperature of the reduction reaction is from 0 ° C to 25 ° C; and/or the organic solvent is selected from the group consisting of methanol and dichloromethane. Tetrahydrofuran, 1,2-dichloroethane; and/or the molar ratio of the compound of the formula (8) to sodium borohydride is 1: (5 to 20).
  18. 如权利要求1所述的方法，其特征在于，步骤(i)中，所述还原反应的温度为0℃～50℃；和/或，所述有机溶剂选自甲醇、乙酸乙酯、乙醇、四氢呋喃；和/或，所述式(4)化合物、三乙胺和钯/碳的摩尔比为1:5:(0.2～0.5)。The method according to claim 1, wherein in the step (i), the temperature of the reduction reaction is from 0 ° C to 50 ° C; and/or the organic solvent is selected from the group consisting of methanol, ethyl acetate, and ethanol. Tetrahydrofuran; and/or the molar ratio of the compound of the formula (4), triethylamine and palladium/carbon is 1:5: (0.2 to 0.5).
  19. 如权利要求1所述的方法，其特征在于，步骤(j)中，所述还原反应的温度为25℃～70℃；和/或，所述有机溶剂选自四氢呋喃、甲苯、二氯甲烷；和/或，所述式(9)化合物与四氢铝锂的摩尔比为1:(5～10)。The method according to claim 1, wherein in the step (j), the temperature of the reduction reaction is from 25 ° C to 70 ° C; and/or the organic solvent is selected from the group consisting of tetrahydrofuran, toluene, and dichloromethane; And/or, the molar ratio of the compound of the formula (9) to lithium tetrahydrogenate is 1: (5 to 10).
  20. 如权利要求1所述的方法，其特征在于，步骤(k)中，所述还原反应的温度为0℃～50℃；和/或，所述有机溶剂选自吡啶、三乙胺、2,6-二甲基吡啶；和/或，所述式(10)化合物、吡啶和乙酸酐的摩尔比为1:(5～10):5。The method according to claim 1, wherein in the step (k), the temperature of the reduction reaction is from 0 ° C to 50 ° C; and/or the organic solvent is selected from the group consisting of pyridine, triethylamine, and 6-lutidine; and/or the molar ratio of the compound of the formula (10), pyridine and acetic anhydride is 1: (5-10): 5.
  21. 一类生物碱化合物，其特征在于，所述生物碱化合物结构如下式(1c)、式(1d)、式(1)、式(ent-1c)、式(ent-1d)、式(ent-1)、式(2)、式(3)、式(4)、式(5)、式(6)、式(7)、式(8)、式(9)所示： A type of alkaloid compound characterized by the following formula (1c), formula (1d), formula (1), formula (ent-1c), formula (ent-1d), formula (ent- 1), Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), and Formula (9):
    Figure PCTCN2017098979-appb-100005
    Figure PCTCN2017098979-appb-100005
  22. 如权利要求21所述的生物碱化合物在制备白坚木属生物碱中的应用。 The use of the alkaloid compound according to claim 21 for the preparation of A. sinensis alkaloid.
PCT/CN2017/098979 2016-11-30 2017-08-25 Method for asymmetrically synthesizing aspidosperma alkaloid WO2018099146A1 (en)

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CN113061072A (en) * 2021-03-30 2021-07-02 郑州药领医药科技有限公司 Method for preparing 1-cyclopropyl naphthalene
CN115925627A (en) * 2022-12-30 2023-04-07 中国科学院昆明植物研究所 Stone pine alkaloid compound with acid sensitive channel inhibition effect and application thereof

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CN110963937A (en) * 2019-12-07 2020-04-07 中国科学院昆明植物研究所 Asymmetric synthesis method of colchicine and allocolchicine
CN110963937B (en) * 2019-12-07 2022-05-06 中国科学院昆明植物研究所 Asymmetric synthesis method of colchicine and allocolchicine
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CN113061072B (en) * 2021-03-30 2023-12-15 郑州药领医药科技有限公司 Method for preparing 1-cyclopropyl naphthalene
CN115925627A (en) * 2022-12-30 2023-04-07 中国科学院昆明植物研究所 Stone pine alkaloid compound with acid sensitive channel inhibition effect and application thereof
CN115925627B (en) * 2022-12-30 2024-06-25 中国科学院昆明植物研究所 Pinus koraiensis alkaloid compound with acid sensitive channel inhibition effect and application thereof

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