Synthetic method for tetracyclic indole skeletons under catalysis of protonic acid

A tetracyclic indole and synthetic method technology, applied in the direction of organic chemistry, can solve the problems of cumbersome routes, harsh experimental conditions, low yield, etc., and achieve the effect of simple preparation of substrates and simple and convenient preparation process

Active Publication Date: 2019-02-26
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] Although there are many types of reported methods, they all have deficiencies in varying degrees, such as cumbersome routes, low yields, harsh experimental conditions and difficult operation, etc. Therefore, it is of great significance to develop a simple and efficient method for preparing tetracyclic indole alkaloid skeleton Significance

Method used

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  • Synthetic method for tetracyclic indole skeletons under catalysis of protonic acid
  • Synthetic method for tetracyclic indole skeletons under catalysis of protonic acid
  • Synthetic method for tetracyclic indole skeletons under catalysis of protonic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Substrate 1-1 (1 mmol) was dissolved in dry dichloromethane (10 mL), and diphenyl phosphate (0.1 mmol, 25 mg) was added under ice-cooling, and reacted under ice-bath for 1 h. After the reaction is completed, use petroleum ether / ethyl acetate (v / v=6 / 1) as the eluent system, and use 200-300 mesh silica gel as the stationary phase to perform column chromatography separation to finally obtain the target compound 1-2. The yield was 82%. Its reaction equation is:

[0046]

[0047]The spectral data of product 1-2 is: HRMS (ESI) m / z: [M+H] + 501.1848; 1 H NMR (600MHz, DMSO-d 6 )δ=7.94(d, J=8.2Hz, 2H), 7.55(d, J=8.2Hz, 2H), 7.39(d, J=7.3Hz, 2H), 7.34(t, J=7.4Hz, 2H) ,7.26(t,J=7.4Hz,1H),6.60(dd,J=8.5,2.5Hz,1H),6.33(d,J=8.5Hz,1H),5.99(s,1H),5.39(d, J=2.5Hz, 1H), 4.24(d, J=15.1Hz, 1H), 4.10–4.06(m, 2H), 3.95(dd, J=9.9, 5.9Hz, 1H), 3.73(td, J=10.7 ,5.6Hz,1H),3.47(s,3H),2.46–2.41(m,4H),2.20(td,J=11.8,8.4Hz,1H),2.01–1.99(m,1H),1.89(dd, J = 16.7, 10.0 Hz, 1H).

Embodiment 2

[0049] Substrate 2-1 (1 mmol) was dissolved in dry dichloromethane (10 mL), and diphenyl phosphate (0.1 mmol, 25 mg) was added under ice-cooling, and reacted under ice-bath for 1 h. After the reaction is completed, use petroleum ether / ethyl acetate (v / v=6 / 1) as the eluent system, and use 200-300 mesh silica gel as the stationary phase to perform column chromatography separation to finally obtain the target compound 2-2. The yield was 72%. Its reaction equation is:

[0050]

[0051] The spectral data of product 2-2 is: HRMS (ESI) m / z: [M+Na] + 527.1151; 1 H NMR (600MHz, DMSO-d 6 )δ=7.95(d,J=8.2Hz,2H),7.58(d,J=8.2Hz,2H),7.38–7.33(m,4H),7.29–7.25(m,1H),7.02(dd,J =8.4,2.1Hz,1H),6.41(d,J=8.4Hz,1H),6.06(s,1H),5.42(d,J=2.1Hz,1H),4.32(d,J=15.3Hz,1H ),4.17(d,J=15.3Hz,1H),4.09–4.01(m,2H),3.67(td,J=10.5,5.6Hz,1H),2.53(d,J=6.0Hz,1H),2.45 (s,3H),2.22(td,J=11.8,8.3Hz,1H),2.03–1.97(m,1H),1.90(dd,J=16.8,9.9Hz,1H)

Embodiment 3

[0053] Substrate 3-1 (1 mmol) was dissolved in dry dichloromethane (10 mL), and diphenyl phosphate (0.1 mmol, 25 mg) was added under ice-cooling, and reacted under ice-bath for 1 h. After the reaction is completed, use petroleum ether / ethyl acetate (v / v=6 / 1) as the eluent system, and use 200-300 mesh silica gel as the stationary phase to perform column chromatography separation to finally obtain the target compound 3-2. Reaction The yield is 75%. Its reaction equation is:

[0054]

[0055] The spectral data of product 3-2 is: HRMS (ESI) m / z: [M+Na] + 571.0638; 1 H NMR (600MHz, DMSO-d 6 )δ=7.95(d, J=8.2Hz, 2H), 7.58(d, J=8.2Hz, 2H), 7.37–7.33(m, 4H), 7.27(t, J=6.7Hz, 1H), 7.15( dd,J=8.4,1.9Hz,1H),6.38(d,J=8.4Hz,1H),6.05(s,1H),5.62(d,J=1.8Hz,1H),4.32(d,J=15.3 Hz, 1H), 4.17(d, J=15.3Hz, 1H), 4.11–4.00(m, 2H), 3.67(td, J=10.7, 5.5Hz, 1H), 2.53(d, J=6.0Hz, 1H ),2.46(s,3H),2.23(dt,J=11.7,8.4Hz,1H),2.06–1.97(m,1H),1.90(dd,J=16.8,9.9Hz,1H);

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Abstract

The invention belongs to the technical field of medicines, and provides a method for synthesizing tetracyclic indole alkaloid skeletons through tandem reactions. The method has a reaction formula which is described in the specification. With the method provided by the invention, reaction substrates are indole-ynamides with different substituents; a catalyst is selected from the group consisting ofcamphorsulfonic acid (CSA), diphenyl phosphate (DPP), p-toluenesulfonic acid (TsOH), p-nitrobenzenesulfonic acid (NsOH) and bistrifluoromethanesulfonimide (HNTf2); a medium needed in the reactions isselected from the group consisting of dichloromethane, dichloroethane, chloroform, toluene, acetonitrile, tetrahydrofuran and acetone; the reactions can be performed under stirring at a low temperature or room temperature; and through the reactions, a series of tetracyclic indole skeleton-containing compounds can be directly produced through tandem cyclization of the indole-ynamide substrates inthe presence of protonic acid. The method provided by the invention has the characteristics of simple operation, wide application range, few by-products, high yield, green reaction, etc.

Description

technical field [0001] The invention relates to a method for efficiently synthesizing a class of tetracyclic indole alkaloid skeleton through protonic acid catalysis. Specifically, it relates to a method for synthesizing a class of tetracyclic indole alkaloid skeleton through series cyclization reaction of indole yne amide substrates with different substituents under the condition of protonic acid catalysis. Background technique [0002] Indole alkaloids are a class of natural products that widely exist in nature in large quantities, with different structures and significant activities. The alkaloids containing tetracyclic skeleton are an important branch of indole alkaloids, and many natural products with this structural unit, such as vinblastine (Vinblastine) and vincristine (vincristine) with anti-tumor activity, have selective Strychnine (Strychnine), which stimulates the spinal cord and enhances the tension of skeletal muscles, has been developed into drugs and is wide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/10
CPCC07D487/00
Inventor 刘永祥程卯生王岩石王晓宇姚博王光辉肖建勇
Owner SHENYANG PHARMA UNIVERSITY
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