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Sinomenine derivative, preparation method and application thereof

A technology of sinomenine and derivatives, applied in the field of polymer compounds

Inactive Publication Date: 2008-09-17
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Throughout the above literature, the structural modification of sinomenine is mainly concentrated in the C and D rings, and new sinomenine derivatives are yet to be discovered.

Method used

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  • Sinomenine derivative, preparation method and application thereof
  • Sinomenine derivative, preparation method and application thereof
  • Sinomenine derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Synthesis of 1, 10-position nitrogen-sulfur six-membered heterocycle

[0077]

[0078]According to the above chemical formula, weigh compound 1: 550mg (1.6mmol) of 1-aminosinomenine, add 4.0ml KSCN (632mg, 2.4mmol) to the glacial acetic acid solution, stir and dissolve, slowly add Br 2 (96mg, 0.6mmol) in 1.5ml of glacial acetic acid solution. Stir at room temperature for 24 h, add 10% NaOH dropwise under ice bath to quench, adjust the pH value to 8.0, and use CHCl 3 Extraction, the obtained organic layer was washed with saturated brine, and then washed with anhydrous NaSO 4 Drying, concentration under reduced pressure, silica gel column separation (CH 3 Cl:CH 3 OH=9:1), the corresponding compound 2 was obtained with a yield of 59%.

[0079] Compound 2:

[0080] 1 H NMR (300MHz, CDCl 3 )δppm 8.45(s, 1H), 7.35(s, 1H), 6.30(s, 1H), 5.85(s, 1H, OH), 5.50(s, 1H), 4.24(d, 1H, J=15.9Hz) , 3.82(s, 3H), 3.29(m, 4H), 3.08(s, 1H), 2.56(m, 1H), 2.44(s, 3H), 2.40(s, 1H), ...

Embodiment 2

[0083] 1-position aminosulfonylation reaction

[0084]

[0085] According to the above chemical formula, weigh compound 1: 550mg (1.6mmol) of 1-aminosinomenine, dissolve in 3ml CH 2 Cl 2 , dropwise added Et 3 N 0.34ml (2.5mmol), add p-toluenesulfonyl chloride 381mg (2.0mmol) under ice-cooling, and stir for 5h under ice-cooling. Pour 30ml CH 2 Cl 2 extraction, the organic layer was washed with saturated brine, and then washed with anhydrous NaSO 4 Drying, concentration under reduced pressure, silica gel column separation (CH 3 Cl:CH 3 OH=9:1), the corresponding compound 3 was obtained with a yield of 52%.

[0086] Compound 3:

[0087] 1 H NMR (300MHz, CDCl 3 )δppm 7.58(d, 2H, J=6.6Hz), 7.25(d, 2H, J=6.6Hz), 6.39(s, 1H), 5.85(s, 1H, OH), 5.39(s, 1H), 4.30 (d, 1H, J=15.9Hz), 3.85(s, 1H), 3.62(s, 3H), 3.47(s, 3H), 3.20(brd, 1H), 3.01(brd, 1H), 2.78(m, 1H), 2.59-2.44(brd, 1H), 2.40(s, 3H), 2.36(s, 1H), 2.19(brd, 3H), 2.03-1.82(m, 4H).

[0088] 13C NMR (300MHz, CDCl ...

Embodiment 3

[0090] Amino acylation reaction at position 1

[0091]

[0092] According to the above chemical formula, weigh compound 1: 550mg (1.6mmol) of 1-aminosinomenine, dissolve in 3ml CH 2 Cl 2 , dropwise added Et 3 N 0.34ml (2.5mmol), add 313mg (2.0mmol) of benzoyl chloride under ice-cooling, and stir for 5h under ice-cooling. Pour 30ml CH 2 Cl 2 extraction, the organic layer was washed with saturated brine, and then washed with anhydrous NaSO 4 Drying, concentration under reduced pressure, silica gel column separation (CH 3 Cl:CH 3 OH=9:1), the corresponding compound 4 was obtained with a yield of 73%.

[0093] Compound 4:

[0094] 1 H NMR (300MHz, CDCl 3 )δppm 7.95(d, 2H, J=7.2Hz), 7.54(d, 1H, J=9.3Hz), 7.53(dd, 2H, J=7.2, 9.3Hz), 6.93(s, 1H), 5.49(s , 1H), 4.39(s, 1H, J=15.9Hz), 3.82(s, 3H), 3.61(brd, 1H), 3.51(s, 3H), 3.40(brd, 1H), 3.10-2.90(m, 4H), 2.65(s, 3H), 2.55-2.48(m, 2H), 2.21-2.05(m, 2H).

[0095] 13C NMR (300MHz, CDCl 3 )δ193.63,152.68,145.79,143.77,1...

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Abstract

The invention aims at acid, alkali and heat labile features of sinomenine molecular structure, and provides an innovative structural reconstruction idea for new chemical synthesis of ring A, ring C, and ring D sinomenine derivatives. The chemical synthetic method includes amination and acylation of 1-position, C-C or C-O connection of 1 position, dicarbonylation and six-membered N heterocyclization of 3-position and 4-position, two molecule sinomenine adduction of connection of 4-hydroxyl and 1-amino, amination and acylation of 6-position, simultaneous amination and x-membered N heterocyclization of 6-position and 7-position, and opening of D ring and terminal amino group modification thereof. The method is novel and unique. The sinomenine derivatives have good antiinflammation activity and bioactivity evaluated by synovial membrane tumor cell (SW982), and can be used in drug and health products for resisting rheumatoid arthritis.

Description

technical field [0001] The invention belongs to the technical field of polymer compounds, and relates to a sinomenine derivative, in particular to a sinomenine derivative and a preparation method and application thereof. Background technique [0002] Sinomenine (sinomenine) is the most effective alkaloid drug clinically used to treat rheumatism, rheumatoid arthritis, joint swelling and other diseases, which is extracted from the rhizomes of the plants of the family Fangjiceae. Anti-inflammatory, analgesic, antihypertensive and anti-cerebral ischemia and other pharmacological effects. [0003] By modifying the structure of sinomenine, it is a current research hotspot to find novel and more active sinomenine derivatives, and the structural modification of sinomenine C ring is the research focus. Yao Zhujun (CN.1687070A, CN.1687065A) synthesized a sinomenine derivative whose C ring is connected with a pyrazine ring and a five-membered heterocycle. Ye Xianrong et al. (Acta Pha...

Claims

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Application Information

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IPC IPC(8): C07D513/08C07D221/28C12P17/12C12P17/18A61K31/54A61K31/485A61P29/00
Inventor 李建新邓张双刘珺
Owner NANJING UNIV
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