Preparation method of aporphine alkaloids and intermediates thereof

A technology for alkaloids and intermediates of aporphim, applied in the field of preparation of natural products and their intermediates, can solve problems such as increasing the complexity of synthetic strategies, and achieve the effects of simple synthetic strategies, economical reactions, and strong substrate applicability

Active Publication Date: 2021-01-19
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The last step is the key step of this synthetic route. Different aporphylloid alkaloids require different synthetic methods due to the different substituents attached to the ring, mainly including the classic Pschorr reaction, oxidative coupling reaction of phenol, and photocyclization. reactions, radical cyclizations, and direct ortho-arylations, which greatly increase the complexity of synthetic strategies

Method used

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  • Preparation method of aporphine alkaloids and intermediates thereof
  • Preparation method of aporphine alkaloids and intermediates thereof
  • Preparation method of aporphine alkaloids and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Dissolve quinoline-2-carboxylic acid (20mmol), naphthalene-1-amine (20mmol, 2.86g) and triethylamine (40mmol, 5.6mL) in CH 2 Cl 2 (40mL), then POCl was added dropwise at 0°C 3 (3.76 mL). The reaction mixture was stirred at 0 °C for 0.5 h. The reaction was then stirred at room temperature for 2 h until the naphthalene-1-amine was consumed. After the reaction was completed, the reaction mixture was cooled to 0 °C, and ice water was slowly added to quench the reaction. Collect the organic phase, then extract the aqueous phase with dichloromethane (3×20 mL), combine the organic phases, wash with saturated NaHCO 3 (2×40mL) aqueous solution, then washed with MgSO 4 dry. The solvent was spin-dried under reduced pressure, and the crude product was recrystallized from dichloromethane / petroleum ether to obtain the target product II-1.

[0040] The reaction formula is as follows:

[0041]

[0042] Product characterization data are as follows:

[0043] N-(Naphthalen-1-yl...

Embodiment 2

[0044] Example 2 Preparation of raw material N-(phenanthren-9-yl)quinoline-2-carboxamide II-2

[0045] The reaction formula is as follows:

[0046]

[0047] step 1:

[0048] To quinoline-2-carboxylic acid (3.46g, 20mmol, 1equiv) and (Boc) 2 To a solution of O (5.68 g, 26 mmol, 1.3 equiv) in 1,4-dioxane (100 mL) was added pyridine (2 mL). Stir for 10 min, add NH in batches 4 HCO 3 (2.06g, 26mmol, 1.3equiv), then stirred at room temperature for 24 hours. After the reaction was complete, the solvent was spin-dried, the residue was dissolved with EtOAc (200 mL), and the organic phase was dissolved with NaHCO 3 (3 x 80 mL) and water (80 mL), dried over anhydrous sodium sulfate, then removed the solvent and dried to give quinoline-2-carboxamide. The structure and characterization data of the product are as follows:

[0049]

[0050]Quinoline-2-carboxamide (CAS no.5382-42-3): 2.96g, 86% yield; white solid; mp=126-128℃; 1 H NMR (400MHz, CDCl 3 )δ8.31(d, J=8.4Hz, 1H), 8....

Embodiment 3

[0055] Embodiment 3 Alkylation reaction

[0056] Under air atmosphere, amide II-1 or II-2 (0.25mmol, 1.0equiv), ethyl bromoacetate (0.5mmol, 84mg), Pd(OAc) 2 (0.025mmol, 6mg), PhCOOK (0.5mmol, 80mg) and 1,2-dichloroethane (2.0mL) were mixed and placed in a 35mL pressure reaction tube with a polytetrafluoroethylene cap. The reaction tube was heated at 90 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through celite, concentrated in vacuo, and the residue was purified with a silica gel column (eluent was petroleum ether and ethyl acetate) to obtain the target product III-1 or III -2.

[0057] The structure and characterization data of compound III-1 are as follows:

[0058]

[0059] Ethyl 2-(8-quoinoline-2-carboxamido)naphthalen-1-yl)acetate(III-1): 83mg; Yield: 86%; Column chromatography gave a white solid (eluent: ethyl acetate / petroleum ether =1 / 6, v / v); mp=128-129°C; 1 H NMR (400MHz, CDCl 3 )δ10.87(s,1H)...

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Abstract

The invention discloses a preparation method of aporphine alkaloid intermediates, wherein the preparation method of the aporphine alkaloid intermediates comprises the steps: under the actions of a palladium catalyst and an additive, carrying out alkylation reaction on N-aryl-quinoline-2-formamide and ethyl bromoacetate to obtain the aporphine alkaloid intermediates. The invention further disclosesvarious aporphine alkaloids with various functional groups and derivatives of the apophenanthrene alkaloids, which can be synthesized by taking the intermediate preparation method as a key step through the steps of reduction, cyclization and the like. Compared with the prior art, the route has the advantages that initial raw materials are easy to obtain, the method is economical and efficient, meanwhile, the substrate applicability is high, various functional groups on the aromatic ring do not influence ring construction, and synthesis of various aporphine alkaloids can be achieved.

Description

technical field [0001] The invention belongs to the field of preparation of natural products and intermediates thereof, and in particular relates to a preparation method of aporphyl alkaloids and intermediates thereof. Background technique [0002] Aporphenanthrene alkaloids are a class of isoquinoline alkaloids widely distributed in nature (formula 1 lists several common aporphenite alkaloids) (Natural Product Research and Development, 2006, 18 (2): 316-324). Studies have shown that aporphyrin alkaloids have good anti-Parkinson's disease (J.Med.Chem.2007,50,171-181), anti-tumor (Anti-Cancer.Agent.Me.2005,5,173-182), anti-viral (Nat.Prod.Res.2009,24,1395-1402), anti-poliovirus (J.Nat.Prod.1998,61,480-484) and other biological activities. [0003] [0004] The core of aporphenanthrene alkaloids is the four-ring skeleton structure of tetrahydrodibenzo[de,g]quinoline. The traditional route for synthesizing the skeleton structure is as follows: in the first step, the amide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48C07D221/14C07D221/18
CPCC07D215/48C07D221/14C07D221/18
Inventor 黄乐浩金红蕾赵承伟杨慧慧
Owner WENZHOU MEDICAL UNIV
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