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Method for synthesizing benzophenanthridine and protoberberine alkaloids through modular diversity regulation and control

A technology of benzophenanthridine and protoberberine, which is applied in the field of organic compound process application, can solve the problems of berberine's poor fat solubility and water solubility, and low bioavailability, and achieve easy-to-obtain raw materials, simple reaction operation, and easy The effect of preparation

Active Publication Date: 2021-05-28
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, limpetine has certain toxicity to the liver, and berberine has poor fat-solubility and water-solubility, resulting in low bioavailability in the body, so the modification of these two types of isoquinoline ring alkaloids very necessary and promising

Method used

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  • Method for synthesizing benzophenanthridine and protoberberine alkaloids through modular diversity regulation and control
  • Method for synthesizing benzophenanthridine and protoberberine alkaloids through modular diversity regulation and control
  • Method for synthesizing benzophenanthridine and protoberberine alkaloids through modular diversity regulation and control

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Synthesis of Compound Q-1:

[0150]

[0151] Add alkenyl bromide compound (2.07g, 8.0mmol, 1.0equiv.), [Ir(COD)Cl] in 250mL one-necked flask 2 (0.27g, 0.4mmol, 5mol%), bis(dicyclohexylphosphinophenyl) ether (0.14g, 0.24mmol, 3mol%), scandium trifluoromethanesulfonate (0.40 g, 0.8mmol, 10mol%). and methanol (80 mL), replaced with nitrogen, and reacted at 60° C. for 12 hours. Spin to dry the solvent, add iodomethane (1.37g, 9.6mmol, 1.2equiv.), potassium carbonate (2.22g, 16.0mmol, 2.0equiv.) and tetrahydrofuran (80mL), 65 ℃, TLC board detects that the reaction of raw materials is complete, stop After the reaction, the solvent was spin-dried, washed with saturated sodium chloride aqueous solution, extracted with ethyl acetate, and separated by column chromatography of the organic phase to obtain 1.03 g (4.6 mmol, 58% yield) of light yellow solid Q-1.

[0152] The relevant characterization results of Q-1 are as follows:

[0153] 1 H NMR (400MHz, CDCl3) δ9.33(s,1H),7...

Embodiment 2

[0155] Synthesis of compound Q-2:

[0156]

[0157] Add alkenyl bromide compound (0.78g, 3.0mmol, 1.0equiv), [Ir(COD)Cl] to 100mL one-necked flask 2 (0.10g, 0.15mmol, 5mol%), bis(dicyclohexylphosphinophenyl) ether (50.7mg, 0.09mmol, 3mol%), scandium trifluoromethanesulfonate (0.15g, 0.3mmol, 10mol%). and methanol (30 mL), replaced with nitrogen, and reacted at 60° C. for 12 hours. Spin to dry the solvent, add p-methoxybenzyl chloride (0.51g, 3.6mmol, 1.2equiv.), potassium carbonate (0.83g, 6.0mmol, 2.0equiv.), tetrabutylammonium iodide (0.22g, 0.6mmol, 20mol%) and tetrahydrofuran (30mL), at 65°C, TLC plate detected that the reaction of the raw materials was complete, the reaction was stopped, the solvent was spin-dried, washed with saturated aqueous sodium chloride solution, extracted with ethyl acetate, and separated by organic phase column chromatography to obtain a light yellow solid Q -2 0.52g (1.6mmol, 52% yield).

[0158] The relevant characterization results of Q-...

Embodiment 3

[0161] Synthesis of Compound Q-3:

[0162]

[0163] Add alkenyl bromide compound (2.07g, 8.0mmol, 1.0equiv.), [Ir(COD)Cl] in 250mL one-necked flask 2 (0.27g, 0.4mmol, 5mol%), bis(dicyclohexylphosphinophenyl) ether (0.14g, 0.24mmol, 3mol%), scandium trifluoromethanesulfonate (0.40 g, 0.8mmol, 10mol%). and methanol (80 mL), replaced with nitrogen, and reacted at 60° C. for 12 hours. Spin to dry the solvent, add dichloromethane (80mL), replace nitrogen, cool down to -78°C, add boron tribromide (6.01g, 2.4mmol, 3.0equiv.), heat up to -30°C, react for 2h, saturated bicarbonate Quenched by aqueous sodium solution, extracted with a mixed solvent of ethyl acetate and tetrahydrofuran, spin-dried the organic phase, added dibromomethane (1.39g, 8.0mmol, 1.0equiv.), potassium carbonate (2.08g, 12.0mmol, 1.5equiv.) and dimethyl Sulfoxide (80mL), nitrogen replacement, 90 ° C, TLC plate detected that the raw material reaction is complete, stop the reaction, washed with saturated aqueous...

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Abstract

The invention discloses a method for synthesizing benzophenanthridine and protoberberine alkaloids through modular diversity regulation and control. The method comprises the following steps: improving a substituent group of a high-iodine salt leaving group, generating pyridine alkyne under the action of relatively mild potassium tert-butoxide, and carrying out [4 + 2] cycloaddition reaction on the pyridine alkyne and diene to obtain polysubstituted isoquinoline ring precursor compounds. Ring opening and aromatization of the isoquinoline ring precursor are realized by developing a novel iridium-catalyzed cross-coupling method, polysubstituted isoquinoline ring compounds with connecting capacity are efficiently synthesized, and then the polysubstituted isoquinoline ring compounds are coupled with a high-activity polysubstituted cyclic boric acid to obtain 3-aryl isoquinoline high-grade intermediates. Through application of two different chemical principles, regulation and control of the 3-aryl isoquinoline high-grade intermediates are realized, and benzophenanthridine and protoberberine alkaloids are modularly, diversely and efficiently synthesized.

Description

technical field [0001] The invention belongs to the technical field of organic compound technology application, and relates to a method for synthesizing triphenanthridines and proberberines alkaloids in a modular and diverse manner. Background technique [0002] As a class of highly active intermediates, aryne has been studied deeply and extensively from the perspective of methodology. After decades of development, the design, synthesis and application of aryne precursors have been gradually applied to the synthesis. Periodic salts, as a new type of pyridyne precursor, have good step economy in preparation, but It is known that the conditions required for the production of pyridyne from periodiodium salts are still relatively harsh, so it is necessary to develop a method with milder conditions. [0003] Isoquinoline compounds are a class of molecules that exist widely and have good activity, and have good prospects in the development of medicine. At present, there are few ...

Claims

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Application Information

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IPC IPC(8): C07D455/03C07D217/16C07D217/22C07D221/18C07D405/04C07D491/056C07D491/08C07D495/08C07F9/576C07F9/62C07F9/6558C07F9/6561
CPCC07D455/03C07D217/22C07F9/62C07D217/16C07D491/056C07D405/04C07F9/65586C07F9/65616C07D221/18C07F9/5765C07D491/08C07D495/08
Inventor 姜雪峰刘凯
Owner EAST CHINA NORMAL UNIVERSITY
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