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A kind of synthetic method of hydrogenated pyridine spiroindoline ring catalyzed by monovalent silver

A technology for hydrogenating a pyridine spiro indole ring and a synthesis method, which is applied in the field of medicine, can solve the problems of poor atom economy, expensive reagents, troublesome post-processing and the like, and achieves low price, short reaction time and simple post-processing. Effect

Active Publication Date: 2021-04-16
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method uses a strong base sodium hydride and a strong reducing agent lithium aluminum hydride, which is dangerous and has poor atom economy.
[0015] In summary, in the known synthetic method of hydropyridine spiroindoline ring, or the reaction conditions need to use a strong base, or the temperature required for the reaction is higher, or the required reagents are expensive, or the post-treatment is troublesome and impact on the environment

Method used

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  • A kind of synthetic method of hydrogenated pyridine spiroindoline ring catalyzed by monovalent silver
  • A kind of synthetic method of hydrogenated pyridine spiroindoline ring catalyzed by monovalent silver
  • A kind of synthetic method of hydrogenated pyridine spiroindoline ring catalyzed by monovalent silver

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Add substrate a1 (0.1mmol, 43mg) and Hans ester (0.2mmol, 51mg) in 25mL eggplant-shaped flask, add 5mL toluene solution, then add silver trifluoromethanesulfonate (0.01mmol, 2.6mg) in toluene The solution was 1 mL, stirred at room temperature, and stirred for 2.5 hours. After the reaction was completed, the target product b1 was separated by flash column chromatography (10:1 ratio of n-hexane: ethyl acetate), and the yield was 99%.

[0042] The reaction formula of Example 1 is:

[0043]

[0044] The spectral data of product b1 is: ESI-MS (m / z): 431[M+H] + ; 1 H-NMR (600MHz, DMSO) δ7.75 (d, J = 8.1Hz, 2H), 7.54 (d, J = 8.1Hz, 2H), 7.14–7.21 (m, 3H), 7.01 (td, J = 7.8 ,1.3Hz,1H),6.88(dd,J=7.8,1.3Hz,2H),6.86(s,1H),6.51(d,J=7.8Hz,1H),6.34(t,J=7.0Hz,1H ),5.86(d,J=7.0Hz,1H),3.62(dt,J=12.0,4.1Hz,1H),3.13(d,J=9.2Hz,1H),3.03–3.08(m,2H),2.61 (s,3H), 2.48(s,3H), 1.81–1.92(m,2H).

Embodiment 2

[0046] Add substrate a2 (0.1mmol, 45mg) and Hans ester (0.2mmol, 51mg) in 25mL eggplant-shaped flask, add 5mL toluene solution, then add silver trifluoromethanesulfonate (0.01mmol, 2.6mg) in toluene The solution was 1 mL, stirred at room temperature, and stirred for 2 hours. After the reaction was completed, the target product b2 was separated by flash column chromatography (n-hexane:ethyl acetate: 15:1), with a yield of 99%.

[0047] The reaction formula of Example 2 is:

[0048]

[0049] The spectral data of product b2 is: ESI-MS (m / z): 449[M+H] + ; 1H-NMR (600MHz, DMSO) δ7.74 (d, J = 8.2Hz, 2H), 7.51 (d, J = 8.2Hz, 2H), 6.97–7.02 (m, 3H), 6.87–6.90 (m, 2H ),6.82(s,1H),6.48(d,J=7.8Hz,1H),6.33(t,J=7.2Hz,1H),5.87(d,J=7.2Hz,1H),3.58(dt,J =12.1, 4.2Hz, 1H), 3.01–3.08(m, 3H), 2.59(s, 3H), 2.46(s, 3H), 1.77–1.89(m, 2H).

Embodiment 3

[0051] Add substrate a3 (0.1mmol, 44mg) and Hans ester (0.2mmol, 51mg) in 25mL eggplant-shaped flask, add 5mL toluene solution, then add silver trifluoromethanesulfonate (0.01mmol, 2.6mg) in toluene The solution was 1 mL, stirred at room temperature, and stirred for 2 hours. After the reaction was completed, the target product b3 was separated by flash column chromatography (n-hexane:ethyl acetate ratio of 10:1), with a yield of 99%.

[0052] The reaction formula of example 3 is:

[0053]

[0054] The spectral data of product b3 is: ESI-MS (m / z): 437[M+H] + ; 1 H-NMR (600MHz, DMSO) δ7.75 (d, J = 8.1Hz, 2H), 7.50 (d, J = 8.1, 2H), 7.23 (dd, J = 5.1, 1.0Hz, 1H), 7.12 (s ,1H),7.00–7.03(m,1H),6.82(dd,J=5.1,3.6Hz,1H),6.55(dd,J=3.6,1.0Hz,1H),6.49(d,J=7.8Hz, 1H), 6.44(t, J=7.2Hz, 1H), 6.26(d, J=7.2Hz, 1H), 3.43–3.49(m, 1H), 3.32–3.37(m, 1H), 3.15(q,J =9.4Hz, 2H), 2.62(s, 3H), 2.43(s, 3H), 1.94(ddd, J = 13.6, 6.8, 2.8Hz, 1H), 1.51–1.57(m, 1H).

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Abstract

The present invention provides a kind of synthetic method that under the action of monovalent silver and reducing agent, the tryptamine alkyne amide substrate containing indole can generate hydrogenated pyridine spiroindoline ring at room temperature, the general reaction formula is as follows , where R 1 , R 2 , R 3 , R 4 As described in the claims and description. The silver catalyst required for the reaction is one of silver trifluoromethanesulfonate, silver hexafluoroantimonate, silver tetrafluoroborate, and silver bistrifluoromethanesulfonimide. The reducing agent required for the reaction is Hans ester. The medium required for the reaction is: toluene. The implementation of the reaction is stirring at room temperature. The method of the invention has easy-to-obtain raw materials, simple operation, wide application range, good atom economy, green reaction and low price.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for synthesizing a hydrogenated pyridine spiroindoline ring, in particular to a tryptamine alkyne amide substrate containing indole under the action of monovalent silver and a reducing agent at room temperature Synthetic method for generating hydrogenated pyridine spiroindoline ring. Background technique [0002] The hydrogenated pyridine spiroindoline ring is a very important structure, which exists in some natural products and active molecules of indole alkaloids, (Angew.Chem.Int.Ed.,2010,49,2000 ., J.Med.Chem., 2013, 56, 9275., Angew.Chem.Int.Ed., 2013, 52, 10204.) In recent years, some active molecules containing this type of structure have been reported continuously, and a simple Effective synthetic methods have become particularly important for the study of their structure-activity relationship. Therefore, this type of structure has become the focus of attention of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/10
CPCC07D471/10
Inventor 刘永祥程卯生庞亚东侯玉乾林敬生林斌肖建勇
Owner SHENYANG PHARMA UNIVERSITY
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