Tetrahydrofuran benzodihydropyran polycyclic compound and application thereof

A technology of chroman and polycyclic compounds, which is applied in the field of pharmaceutical synthesis chemistry, can solve the problems of poor chemical selectivity and long reaction time, and achieve high yield, short preparation route and low synthesis cost Effect

Inactive Publication Date: 2014-02-05
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2012, the Reddy research group also reported the tetrahydrofuranochroman ring constructed by intramolecular Prins cycliza

Method used

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  • Tetrahydrofuran benzodihydropyran polycyclic compound and application thereof
  • Tetrahydrofuran benzodihydropyran polycyclic compound and application thereof
  • Tetrahydrofuran benzodihydropyran polycyclic compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1 prepares compound 5a of the present invention

[0025] Weigh trans-phenylnitroalkene 3a (0.20mmol), rhodium acetate (1.70mg, 0.004mmol), 5-bromo-ortho-substituted benzaldehyde 2a (0.30mmol), Molecular sieves (70 mg) were put into a small test tube reactor, and 1.0 mL of redistilled dichloromethane was added at room temperature. N-Methylisatin diazo 1a (0.30mmol) was dissolved in 0.7mL redistilled dichloromethane, and injected into the reaction system through a peristaltic pump for 1 hour. After the injection was completed, DBU (0.04mmol) was added, and the reaction was continued for 2h , the reaction was completed, and the solvent was removed by rotary evaporation at 40°C, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:50 ~ 1:20) to obtain tetrahydrofuranochroman compound 5a. Yield 56%, dr 82:18. See Table 1.

[0026]

[0027] Characterization of the product tetrahydrofuranochroman compound 5a:

[0028] 1 H ...

Embodiment 2-19

[0030] Embodiment 2-19 prepares compound (5b~5s)

[0031] Embodiment 2-19 is the same as embodiment 1. See Table 1 for the changes of substituents, compound number, d.r. value, yield, etc. in the reaction.

[0032] Table 1

[0033]

[0034] The characterization of the product tetrahydrofuranochroman compound 5b-5s is as follows:

[0035] Characterization of 5b:

[0036] 1 H NMR (400MHz, CDCl 3 , 25℃, TMS): δ=8.03(d, J=8.1Hz, 1H), 7.72(d, J=2.2Hz, 1H), 7.55-7.17(m, 8H), 6.91(dd, J=11.0, 8.2Hz, 4H), 4.94-4.86(m, 1H), 3.83(d, J=2.5Hz, 4H), 3.28-3.08(m, 1H), 2.94(dd, J=17.6, 8.4Hz, 1H), 2.30(s, 3H);

[0037] 13 C NMR (400MHz, CDCl 3 ,25℃,TMS):δ=175.94,171.23,169.56,153.29,140.15,133.52,131.45,130.07,129.49,129.17,128.99,126.38,125.51,123.63,120.41,119.01,116.68,115.17,93.11,86.20,76.63 , 75.99, 62.89, 54.29, 47.64, 34.93, 26.32.

[0038] Characterization of 5c:

[0039] 1 HNMR (400MHz, CDCl 3 , 25℃, TMS): δ=7.93(d, J=7.0Hz, 1H), 7.43(d, J=8.7Hz, 1H), 7.39-6.96(m, ...

Embodiment 20 4

[0089] Example 20 Inhibition of Histone Deacetylase Activity by Tetrahydrofuranochromanane Polycyclic Compounds 5a-5s

[0090] Histone deacetylase (HDAC) is a class of proteases that play an important role in the structural modification of chromosomes and the regulation of gene expression. In cancer cells, overexpression of HDAC leads to enhanced deacetylation, which increases the attractive force between DNA and histones by restoring the positive charge of histones, making the relaxed nucleosomes very compact, which is not conducive to specific genes expression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACi) can regulate the expression and stability of apoptosis and differentiation-related proteins by increasing histone acetylation in specific regions of chromatin, and induce apoptosis and differentiation. Become a new class of anticancer drugs.

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PUM

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Abstract

The invention discloses a tetrahydrofuran benzodihydropyran polycyclic compound shown as a formula (I). The tetrahydrofuran benzodihydropyran polycyclic compound is prepared by the following steps: performing 3+2 cycloaddition on isatin diazo, ortho-substituted benzaldehyde and nitrophenyl alkene under the catalysis of rhodium acetate to construct a multi-substituted tetrahydrofuran intermediate; adding a base and performing intramolecular Michael addition to further cyclize so as to synthesize the tetrahydrofuran benzodihydropyran polycyclic compound. The compound has excellent inhibitory activity on histone deacetylase.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry and relates to a polycyclic compound of tetrahydrofurochroman. Background technique [0002] Tetrahydrofuranochroman ring is an important skeleton structure of special medicinal compounds, and is often found in flavonoids, catechols, and pterostilbene natural products. For example, Cordigol was first isolated in 1988 by Hostettmann's research group from the cortex of a plant called Cordia goetzei Guerke (Org. Lett., 2010, 12, 5; Tetrahedron Lett. 1998, 39, 141 ), and found to have good antibacterial activity. Therefore, it is of great significance to develop new tetrahydrofuranochroman rings. [0003] [0004] In 2010, the Spivey research group reported the method of Prins cyclization involving oxonium to construct the tetrahydrofuranochroman ring, but it must be carried out at -78°C, and the conditions are very harsh (Org.Lett., 2010, 12 , 5). In 2012, the Reddy ...

Claims

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Application Information

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IPC IPC(8): C07D491/20A61P35/00
CPCC07D491/20
Inventor 刘顺英王冬伟邱林胡文浩
Owner EAST CHINA NORMAL UNIVERSITY
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