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Sinomenine derivate and preparation method and application thereof

A technology of sinomenine and its derivatives, which is applied in the field of drug synthesis, can solve rare problems, and achieve the effects of low cytotoxicity, good transdermal performance, and mild reaction conditions

Inactive Publication Date: 2013-03-13
HUNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, there are still very few reports on the simultaneous modification of the 1 and 4 positions of sinomenine A ring and the improvement of transdermal absorption of sinomenine.

Method used

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  • Sinomenine derivate and preparation method and application thereof
  • Sinomenine derivate and preparation method and application thereof
  • Sinomenine derivate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the synthesis of compound 1a

[0040] Using pyridine as solvent, 0.246g (0.684mmol) sinomenine benzyl alcohol intermediate and 1mL acetic anhydride were refluxed for 3h under the catalysis of DMAP; pyridine was evaporated under reduced pressure, and saturated sodium bicarbonate solution was added to adjust the pH value to 8~9 Finally, extract with chloroform; the organic phase is washed with water several times and then dried with anhydrous sodium sulfate. The organic phase is evaporated and spin-dried under reduced pressure, and the residue is separated and purified by column chromatography [V (dichloromethane): V (methanol )=30:1] to obtain compound 1a. Yield 85.2%.

[0041] Compound 1a: pale yellow solid, mp.56~58°C; 1 H NMR (400MHz, CDCl 3 )δ=1.86~1.93(m,1H),2.11(s,3H),2.04~2.16(m,2H),2.36(s,3H),2.43(s,3H),2.51~2.55(m,2H) ,2.66(dd,J 1 =6.0Hz&J 2 =18.8Hz,1H),3.02(t,J=7.2Hz,2H),3.27(t,J=4.0Hz,1H),3.48(s,3H),3.76(s,3H),3.89(d,J =16.0Hz,1H),5.07(s,2...

Embodiment 2

[0042] Embodiment 2: the synthesis of compound 1b:

[0043] The procedure is the same as in Example 1, 0.248g, (0.684mmol) sinomenine benzyl alcohol intermediate and 1.5mL propionic anhydride were used as raw materials to prepare compound 1b. Yield 75.2%.

[0044] Compound 1b: pale yellow solid, mp.58~60°C; 1 H NMR (400MHz, CDCl 3 ):δ=1.29(t,J=7.6Hz,3H),1.59~1.62(m,1H),1.71(t,J=7.6Hz,3H),1.83~1.94(m,2H),2.04~2.09( m,1H),2.38(q,J=7.6Hz,2H),2.42(s,3H),2.49~2.54(m,2H),2.57~2.73(m,3H),2.99~3.03(m,2H) ,3.26(t,J=4.0Hz,1H),3.48(s,3H),3.74(s,3H),3.89(d,J=16.0Hz,1H),5.08(d,J=2.0Hz,2H) ,5.46(d,J=1.6Hz,1H),6.85(s,1H). 13 C NMR (100MHz, CDCl 3 ):δ=9.14,20.85,27.59,27.89,36.92,40.74,42.68,45.61,46.63,50.09,54.80,55.94,56.01,64.02,112.34,114.76,128.69,130.31,130.53,139.72,149.63,152.50,174.05, 192.19.MS(EI)m / z(%):471.3(M + ,93).

Embodiment 3

[0045] Embodiment 3: the synthesis of compound 2a

[0046] With DMF as solvent, in Cs 2 o 3 Under catalysis, 0.347g (0.966mmol) of sinomenine benzyl alcohol intermediate and 0.27ml (2.90mmol) of 1-bromopropane were stirred and reacted at 60°C for 2h; after filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography Compound 2a was obtained by separation and purification [V (dichloromethane): V (methanol) = 15: 1]. Yield 80.6%.

[0047] Compound 2a: colorless oil; 1 H NMR (400MHz, CDCl 3 ):δ=1.04(t,J=7.6Hz,3H),1.83~1.90(m,2H),1.95~1.98(m,1H),2.03~2.15(m,3H),2.42(bs,1H), 2.50(s,3H),2.53(d,J=16.0Hz,2H),2.72~2.80(m,2H),3.07~3.11(m,1H),3.21(s,1H),3.41(t,J= 4.0Hz,1H),3.48(s,3H),3.80(s,3H),3.97~4.10(m,2H),4.21(d,J=16.0Hz,1H),4.61(q,J=10.8Hz, 2H),5.45(d,J=1.6Hz,1H),6.87(s,1H). 13 C NMR (100MHz, CDCl 3 ):δ=10.44,20.96,23.53,36.79,40.81,42.57,45.41,47.20,49.69,54.84,55.79,56.34,63.43,73.80,111.69,114.90,130.18,132.053,14...

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Abstract

The invention discloses a sinomenine derivate and a preparation method and an application thereof. The preparation method comprises the following steps: carrying out a reaction on the sinomenine or hydrochloride thereof and paraformaldehyde to obtain a sinomenine benzyl alcohol midbody; carrying out an esterification reaction on the obtained sinomenine benzyl alcohol midbody and C2-4 carboxylic acid anhydride to prepare the product; or, carrying out a substitution reaction on the obtained sinomenine benzyl alcohol midbody with 1-bromo-C2-4 alkane to prepare the product. Applied to preparing the medicine with the anti-inflammatory and immune regulation effects, the obtained sinomenine derivate has transdermal performance better than sinomenine and has a certain anti-inflammatory activity. The derivate is expected to be applied to treating immune diseases such as rheumatic disease and rheumatoid disease.

Description

technical field [0001] The invention relates to a sinomenine derivative and its preparation method and application, belonging to the field of drug synthesis. Background technique [0002] Qingfengteng is the dry cane of Sinomenium acutum (Thunb.) Rehd.et Wils.] and Sinomenium acutum (Thunb.) Rehd.et Wils.Var.Cinereum Rehd.et Wils.], As a traditional Chinese medicine in my country, it has a history of more than a thousand years in the treatment of rheumatic diseases. In the 1920s, Ishiwari (Journal of chemical society Abstracts, 1921, 1354.) extracted the active ingredient sinomenine (sinomenine) for the treatment of rheumatic diseases from Japanese Teng Teng for the first time. In the 1960s, Chinese scholar Zhu Renhong first discovered sinomenine from domestic Qingfengteng. [0003] Sinomenine is an isoquinoline alkaloid, and it is a therapeutic drug for rheumatic and rheumatoid arthritis with definite clinical curative effect. However, during the course of medication, it ...

Claims

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Application Information

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IPC IPC(8): C07D221/28A61K31/485A61P29/00A61P37/02
Inventor 安德烈赵子剑肖竟彭志鸿谢德逊蔡青云
Owner HUNAN UNIV
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