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Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof

A technology of coumarin skeleton and polycyclic compounds, which is applied in the field of medicinal chemistry, can solve problems such as no relevant reports, and achieve the effects of good atom economy, mild reaction conditions, and simple operation

Active Publication Date: 2013-11-27
ARMY MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no relevant reports on the preparation of chiral coumarin polycyclic compounds through asymmetric catalytic methods, especially through green and environmentally friendly organic small molecule catalysis.

Method used

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  • Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof
  • Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof
  • Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] In a clean 10ml reaction tube, add chiral prolinol silyl ether catalyst (0.02mmol, 14.8mg), 3-acetylcoumarin (0.1mmol, 18.8mg), 4-phenyl-2,4 -Hexadienal (0.2mmol, 34mg), L-Boc-2-phenylglycine (0.02mmol, 5mg) and chloroform (0.5mL), stirred and reacted at 0°C for 42 hours, after the reaction was monitored by TLC, added DBU (0.05mmol, 7.5μL), stirred at 25°C for 2 hours, then added TEA (0.5mmol, 70μL) and MsCl (0.2mmol, 15.5μL) at 0°C and stirred for 15 minutes, recovered the solvent under reduced pressure, and the residue was passed through The product P1 was separated by column chromatography and named as (3aR,7aS,13bR)-3-phenyl-1,3a,4,13b-tetrahydronaphtho[8a,1-c]benzopyran-7,8- Diketone, yield rate is 87%, structural formula is as follows:

[0036]

[0037] [α] D 20 =+152.4(c=0.42in CHCl 3 ); 90%ee, chiral test conditions HPLC analysis [Daicel chiralpak AD, n-hexane / i-PrOH=80 / 20, 1.0mL / min, λ=254nm, t(major)=18.53min, t(minor) =11.84min];

[0038] 1 H NMR (4...

Embodiment 2

[0042] In a clean 10ml reaction tube, add chiral prolinol silyl ether catalyst (0.02mmol, 14.8mg), 6-bromo-3-acetylcoumarin (0.1mmol, 26.7mg), 4-phenyl -2,4-Hexadienal (0.2mmol, 34mg), L-Boc-2-phenylglycine (0.02mmol, 5mg) and chloroform (0.5mL), stirred the reaction at 0°C for 72 hours, and monitored the reaction by TLC After the end, add DBU (0.05mmol, 7.5μL), stir at 25°C for 2 hours, then add TEA (0.5mmol, 70μL) and MsCl (0.2mmol, 15.5μL) at 0°C and stir for 15 minutes, then recover the solvent under reduced pressure , the residue was separated by column chromatography to obtain the product P2 name: (3aR,7aS,13bR)-12-bromo-3-phenyl-1,3a,4,13b-tetrahydronaphtho[8a,1-c] The yield of benzopyran-7,8-dione is 76%. The structural formula is as follows:

[0043]

[0044] [α] D 20 =+162.9(c=0.80in CHCl 3 );87%ee, chiral test conditions HPLC analysis[Daicel chiralpak AD,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(major)=19.07min,t(minor) =17.72min];

[0045] 1 H NMR (400MHz...

Embodiment 3

[0049] In a clean 10ml reaction tube, add chiral prolinol silyl ether catalyst (0.02mmol, 14.8mg), 6-chloro-3-acetylcoumarin (0.1mmol, 22.2mg), 4-phenyl -2,4-Hexadienal (0.2mmol, 34mg), L-Boc-2-phenylglycine (0.02mmol, 5mg) and chloroform (0.5mL), stirred the reaction at 0°C for 12 hours, and monitored the reaction by TLC After the end, add DBU (0.05mmol, 7.5μL), stir at 25°C for 2 hours, then add TEA (0.5mmol, 70μL) and MsCl (0.2mmol, 15.5μL) at 0°C and stir for 15 minutes, then recover the solvent under reduced pressure , the residue was separated by column chromatography to obtain the product P3 name: (3aR,7aS,13bR)-12-chloro-3-phenyl-1,3a,4,13b-tetrahydronaphtho[8a,1-c] The yield of benzopyran-7,8-dione is 83%. The structural formula is as follows:

[0050]

[0051] [α] D 20 =+204.4(c=0.78in CHCl 3 );87%ee, chiral test conditions HPLC analysis[Daicel chiralpak AD,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(major)=20.04min,t(minor) =18.11min];

[0052] 1 H NMR (400M...

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Abstract

The invention relates to a coumarin skeleton polycyclic compound with biological activity as well as a preparation method and use thereof. The general formula structure of the compound is as shown in the specification, wherein in the formula, * represents a chiral carbon atom, R1 and R2 are respectively any one of C1-C16 alkyl, heteroaromatic ring or substituted aromatic ring; R3 is any one of H or C1-C16 alkyl or aryl; R4-R7 are respectively any one of H, F, Cl, Br, ester group, cyano, sulfuryl, nitro, heteroaromatic ring, C1-C16 oxyl, C1-C16 alkyl or substituted aromatic ring, and X is any one of O, X N, S atoms or imine, ketoxime and aromatic hydrazone. The compound has excellent region and stereoselectivity and a plurality of special physiological activities and tumor cell proliferation inhibition activities, and can be used for researching and developing antitumor drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a biologically active coumarin skeleton polycyclic compound, its preparation method and application. Background technique [0002] Coumarin skeletons, especially polycyclic compounds based on such skeleton structures, are widely found in natural products and pharmaceutical intermediates. The important role of these compounds in medicine has attracted more and more chemists' interest. The modification of substituents of these compounds, the synthesis of structural analogs and their biological activities have become research hotspots. [a) S.M.Sethna, N.M.Shah, Chem.Rev.1945,36,1;b)S.V.Ukhov,M.E.Kon'shin,T.F.Odegova,Pharm.Chem.J.2001,35,364;c)B.Musicki,A.M.Periers , P. Laurin, D. Ferroud, Y. Benedetti, S. Lachaud, F. Chatreaux, J. L. Haesslein, A. Iltis, C. Pierre, J. Khider, N. Tessot, M. Airault, J. Demassey, C. Dupuis-Hamelin, P. Lassaigne, A. Bonnefoy, P. Vicat, M. Klich, Bi...

Claims

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Application Information

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IPC IPC(8): C07D311/96A61K31/37A61P35/00
Inventor 陈应春何凤田马超连继勤蒋坤
Owner ARMY MEDICAL UNIV
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