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Sinomenine derivative and preparation method and applications thereof

A technology of sinomenine and its derivatives, applied in the field of sinomenine derivatives and its preparation, can solve the problems of no report on the structure modification of sinomenine, and achieve good anti-inflammatory effect

Inactive Publication Date: 2011-01-19
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there is still a lot of space for the structural modification of the 1-position of the A ring of sinomenine, and the structural modification of sinomenine using the current popular microfluidic synthesis technology has not been reported so far

Method used

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  • Sinomenine derivative and preparation method and applications thereof
  • Sinomenine derivative and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the synthesis of 1-chlorosinomenine

[0029] Dilute the chemically pure Antiformin solution to 25% (v / v), slowly add 50mL dropwise to 20mL aqueous solution of 2g sinomenine hydrochloride 1 within 10min under stirring, after the dropwise addition is completed , adjust pH=9~10 with hydrochloric acid, extract with dichloromethane (3×20mL), wash with anhydrous Na 2 SO 4 Drying, rotary evaporation, to obtain crude product, column chromatography purification (DCM / CH 3 OH, v / v=15:1) to obtain 1-chlorosinomenine 1, yield: 58%.

[0030]

[0031] mp: 179~181℃; ESI-MSm / z: 364, 366[M+H] + ; 1 HNMR (300MHz; CDCl 3 ; TMS) δ: 6.72 (1H, s), 5.48 (1H, d, J = 1.8Hz), 4.37 (1H, d, J = 15.6Hz), 3.76 (3H, s), 3.49 (3H, s), 3.32(1H, m), 3.09(1H, m), 3.05(1H, m), 2.53(3H, m), 2.42(3H, s), 1.96(3H, m)ppm; 13 CNMR (75MHz; CDCl 3 ; TMS) δ: 193.7, 152.3, 145.3, 143.5, 127.4, 124.0, 122.9, 114.6, 110.0, 56.0, 55.9, 54.8, 48.9, 46.8, 45.4, 42.6, 40.7, 35.5, 22.8ppm.

Embodiment 2

[0032] Embodiment 2: the synthesis of 1-bromosinomenine

[0033]At room temperature, dissolve 2.2g sinomenine in 50mL of dichloromethane, slowly add 1.25g of NBS within 5min under stirring, continue the reaction at 50°C for 30min, after cooling, add 40mL of Na 2 S 2 o 3 The saturated solution was stirred for 5 min, and the dichloromethane layer was separated, washed with an appropriate amount of water and saturated brine, and washed with anhydrous Na 2 SO 4 After drying and rotary evaporation, 1-bromosinomenine 2 was obtained as a pale yellow solid with a yield of 93%.

[0034]

[0035] mp: 134-136°C; ESI-MS m / z: 407, 408 [M-H] - ; 1 HNMR (300MHz; CDCl 3 ; TMS) δ: 6.92 (1H, s), 5.44 (1H, d, J = 1.8Hz), 4.34 (1H, d, J = 15.6Hz), 3.81 (3H, s), 3.50 (3H, s), 3.33(1H, m), 3.12(1H, m), 3.01(1H, d, J=18.9Hz), 2.62(1H, m), 2.48(5H, m), 1.97(3H, m)ppm; 13 CNMR (75MHz; CDCl 3 ; TMS) δ: 193.8, 152.8, 146.0, 144.5, 128.9, 124.6, 114.5, 113.6, 113.4, 57.0, 56.5, 55.2, 49.1, 47...

Embodiment 3

[0036] Embodiment 3: the synthesis of 1-iodosinomenine

[0037] In 80mL of dichloromethane, add 3.29g (10mmol) of sinomenine, after dissolving, add 2.25g (10mmol) of N-iodosuccinimide, stir at room temperature for 2 hours, add an appropriate amount of saturated sodium thiosulfate solution Wash the dichloromethane solution, and then wash the dichloromethane solution with saturated brine (3×20mL), dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and separate on a silica gel column. The developing solvent is: dichloromethane / methanol to obtain 1- Iodosinomenine 3 (4.14 g, 92% yield).

[0038]

[0039] Yield: 92%; mp: 106-108°C; ESI-MSm / z: 454[M-H]-; 1HNMR (300MHz; CDCl3; TMS) δ: 7.16 (1H, s), 6.58 (1H, br), 5.44 (1H, s), 4.35(1H, d, J=15.6Hz), 3.80(3H, s), 3.50(3H, s), 3.37(1H, m), 3.14(1H, m), 2.90(1H, d, J=18.9Hz), 2.66 (1H, m), 2.49 (5H, m), 2.00 (3H, m) ppm; 13CNMR (75MHz; CDCl3; TMS) δ: 194.0, 152.6, 146.1, 145.5, 132.3, 124.7, 119.6, 115.0, 88.1, ...

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Abstract

The invention discloses a sinomenine derivative and a synthesis method and aapplications thereof, wherein halogen, carbon-carbon double bond substituent and isoxazoline heterocyclic ring substituent are introduced to the 1-site of the sinomenine ring A. When the sinomenine derivative is prepared, sinomenine is used as the matrix and the synthesis technology containing microfluidic synthesis is adopted to perform Heck reaction and 1,3-dipolar cycloaddition reaction on the 1-site of sinomenine and generate the sinomenine derivative. The obtained compound has better anti-inflammatory activity and is potential to be used for curing arthritis and rheumatoid arthritis and used in the anti-inflammatory medicines thereof.

Description

technical field [0001] The present invention relates to sinomenine derivatives and their preparation methods and applications. Background technique [0002] Sinomenine [(9α, 13α, 14α)-7,8-didehydro-4-hydroxy-3, 7-dimethoxy-17-methyl-mophinan-6-one, Sinomenine] is derived from Ivy and Ivy An isoquinoline alkaloid extracted from dried canes, sinomenine and its derivatives have analgesic and sedative, antitussive and local anesthesia, blood pressure lowering and anti-inflammatory effects, and are strong histamine release agents in plants. It is clinically used to treat rheumatism and rheumatoid arthritis; animal experiments suggest that it has a protective effect in shock and organ damage. Its structural formula is as follows: [0003] Through the structural modification of sinomenine, the synthesis of derivatives with novel structures and higher screening activity is one of the current research hotspots in medicinal chemistry. Such as Chen Lei et al. "Microbiological transf...

Claims

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Application Information

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IPC IPC(8): C07D221/28C07D413/04A61K31/485A61P19/02A61P29/00B01J19/00
Inventor 金杰李建新
Owner NANJING UNIV
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