Method for synthesizing 6-6 fused ring structure in berberine and ebony natural product

A natural product, berberine technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems that hinder the development and application of the pharmaceutical field, such as harsh conditions and high costs, and achieve the promotion of extensive development and application, mild reaction conditions, and production low cost effect

Inactive Publication Date: 2016-07-27
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This route requires a total of 6 steps of reaction, with a total yield of 38%, but on the whole, the operation is still relatively cumbersome, the selectivity is poor, and the yield is still not high enough, and some steps in the preparation process require higher reaction conditions. are not readily available, so overall, this route is still not suitable for industrial production
[0011] In summary, although the berberine and ebony compounds with 6-6 acyclic structure containing tetrahydropyridine-2-carbonylpyridine have good biological activity, due to the harsh conditions, The disadvantages of cumbersome operation, high cost, low yield, and unsuitability for industrial production have seriously hindered its development and application in the field of medicine.

Method used

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  • Method for synthesizing 6-6 fused ring structure in berberine and ebony natural product
  • Method for synthesizing 6-6 fused ring structure in berberine and ebony natural product
  • Method for synthesizing 6-6 fused ring structure in berberine and ebony natural product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: preparation of

[0038]

[0039] 1) Take methyl salicylate 1 (1.7mL, 13.1mmol) in a 100mL round bottom flask, add 60mL (0.2M) of dichloromethane, add 5.5mL triethylamine and 3.3mL trifluoromethane dropwise at 0°C Sulfonic anhydride, then reacted at 0°C for 2 hours, added water, extracted with ethyl acetate, combined the extracts, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, column chromatography (3% ethyl acetate / petroleum ether) to obtain a light yellow liquid, namely: compound 2 (3.3 g, yield 89%), Rf=0.56 (20% ethyl acetate-petroleum ether).

[0040] 2) Weigh known compound 2 (63mg, 0.22mmol) and compound 3 (100mg, 0.33mmol) in a 25mL round bottom flask, add 13mg tetraphenylphosphine palladium, 250mg tetrabutylammonium iodide, 2mg iodide Cuprous, under the protection of nitrogen, add 4.5mL (0.1M) deoxygenated triethylamine / acetonitrile (1 / 4), react at 80°C for 33 hours, filter w...

Embodiment 2

[0045] Example 2: preparation of

[0046]

[0047] 1) Weigh compound 6 (325mg, 1.33mmol) in a 100mL round bottom flask, add 6.6mL acetonitrile, 27mL silver nitrate aqueous solution (0.1N), 6.6mL10% sodium hydroxide aqueous solution, react at room temperature for 23 hours, diatoms Filter with soil, add 6N aqueous sodium hydroxide solution to adjust the pH value to less than 5, extract with ethyl acetate, combine the extracts, wash once with 1N aqueous hydrochloric acid solution, dry over anhydrous sodium sulfate, filter, and spin to dry the solvent;

[0048] The resulting crude product was directly dissolved in 6.6mL (0.2M) N,N-dimethylformamide, 110mg potassium carbonate and 0.15mL dimethyl sulfate were added, and reacted at room temperature for 2 hours. Extract the ester, combine the extracts, wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, spin to dry the solvent, and column chromatography (20% ethyl acetate / petroleum ether) to ob...

Embodiment 3

[0054] Example 3: preparation of

[0055]

[0056] 1) Weigh commercially available raw material compound 9 (360mg, 2.3mmol) and dissolve it in 5.7mL (0.4M) of N,N-dimethylformamide, add 42mg of 4-dimethylaminopyridine and 0.5mL of ethanol, and slowly Add 1.1 g of dicyclohexylcarbodiimide, react at room temperature for 8 hours, filter through diatomaceous earth, spin to dry the solvent, and perform column chromatography (10-20% ethyl acetate / petroleum ether) to obtain a light yellow solid, namely: Compound 10 (208 mg, 49% yield), Rf=0.40 (30% ethyl acetate-petroleum ether).

[0057] 2) Weigh compound 10 (51mg, 0.28mmol) and compound 3 (80mg, 0.26mmol) used in Example 1 in a 10mL round bottom flask, add 10mg dichlorodibenzonitrile palladium, 15mg tri-tertiary tetrafluoroborate Butylphosphine, 3mg cuprous iodide, 290mg tetrabutylammonium iodide, add 2.6mL (0.1M) deoxygenated triethylamine / acetonitrile (1 / 4) under nitrogen protection, and react at 80°C for 5 hours , filtere...

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PUM

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Abstract

The invention discloses a method for synthesizing a 6-6 fused ring structure in berberine and ebony natural products. The method comprises the step of carrying out intramolecular tandem cyclization reaction on conjugated enyne ester with a structure shown in a formula II in a solvent, so that the 6-6 fused ring structure shown in a formula I is obtained, a specific reaction formula is described in the specification, wherein R1 and R2 are respectively independently selected from hydrogen, alkyl, naphthenic base, aryl and heterocyclic radical; or R1 and R2 form a saturated or unsaturated carboatomic ring or heterocyclic ring together; R3 and R4 are respectively independently selected from hydrogen, alkyl, naphthenic base, aryl and heterocyclic radical; or R3 and R4 form a saturated or unsaturated carboatomic ring or heterocyclic ring together; R is selected from C1-C4 alkyl; P is an amino-protecting group. The method disclosed by the invention has the advantages of simple operation, safety, environmental friendliness, low production cost, high yield and adaptability to large scale production and has important value in promotion of extensive use of the compound in the filed of medicines.

Description

technical field [0001] The invention relates to a method for synthesizing a 6-6 asymmetric ring structure in natural products of the genus berberine and ebony, belonging to the technical field of organic synthesis. Background technique [0002] 6-6-Alkane Structures Containing Tetrahydropyridine-2-Carbonylpyridine in Natural Products of Berberine and Ebony Such compounds have good antibacterial and anti-inflammatory activities; for example: natural products Oxypalmatine and Berlambine of the genus Berberine, and natural products Norketoyobyrine and Naucleficine of the genus Ebony, all of which have good antibacterial and anti-inflammatory activities and have been used in traditional Chinese medicine Among them, the structural formulas of the above compounds are as follows: [0003] [0004] At present, there are few reports on the methods of synthesizing the 6-6 asymmetric ring structure in natural products of berberine and ebony, and the main synthetic routes are as fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03C07D471/14C07D471/22
CPCY02P20/55C07D455/03C07D471/14C07D471/22
Inventor 欧劲桀李科高栓虎
Owner EAST CHINA NORMAL UNIV
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