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Chiral 2,5-pyrroline derivative, and synthetic method and biological activity thereof

A technology of dihydropyrrole and derivatives, applied in the field of chirality, which can solve the problems of uneconomical and easy availability of chiral raw materials, cumbersome operation, and limited methods

Inactive Publication Date: 2012-02-15
UNIV OF SCI & TECH OF CHINA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the methods reported in the literature for the synthesis of chiral 2,5-dihydropyrrole derivatives are very limited, mainly olefin metathesis via aminolysis / ring closure of optically pure vinyl epoxides (Synlett 2002, 731) and the sequential Wittig-Horner / intramolecular Michael addition / reverse Diels-Alder reaction (Tetrahedron 1996, 52, 6943) starting from optically pure hydroxyamides
However, these methods all use optically pure starting materials and multi-step reactions to construct chiral 2,5-dihydropyrrole skeletons, which have limitations such as uneconomical and easy-to-obtain chiral raw materials and cumbersome operations.

Method used

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  • Chiral 2,5-pyrroline derivative, and synthetic method and biological activity thereof
  • Chiral 2,5-pyrroline derivative, and synthetic method and biological activity thereof
  • Chiral 2,5-pyrroline derivative, and synthetic method and biological activity thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The (R)-type chiral phosphoric acid catalyst represented by 0.12mmol of 4-nitrobenzaldehyde, 0.1mmol of 2-aminomalonate, 0.01mmol of formula 1, 100mg Molecular sieves (purchased from Tianjin Alpha Aisha Co., Ltd.) were put into a 10 mL glass reaction test tube, 1 mL of toluene was added, stirred at room temperature for 10 minutes (600 rpm / min), then cooled to -10 °C, and then 0.5 mmol of 3-butylene was added Alkyn-2-one, react at -10°C for 30 hours.

[0057] Then, 4 mL of ethyl acetate was added to the test tube containing the reaction mixture to dilute the reaction mixture. Spread a layer of thin-layer chromatography silica gel H on a glass funnel plugged with cotton, pump the silica gel tightly with a water pump, then pour the reaction mixture in the test tube into the funnel, and filter out molecular sieves, including molecular sieves. A layer of chromatographic silica gel remains in the funnel as a filter cake. Next, after washing the suction-filtered filter cake...

Embodiment 2

[0062] Adopt the method identical with embodiment 1, wherein: the aldehyde that adopts is 3-nitrobenzaldehyde, add thin-layer chromatography silica gel H in common glass column, pressurize column chromatography with nitrogen (column length 15 centimetres, flow velocity 3 drop / second), the eluent was petroleum ether: ethyl acetate 6:1 (volume ratio), and the product 5ab was obtained with a yield of 88% and an ee of 92%.

[0063] Characterization data of compound 5ab:

[0064]

[0065] (R)-Diethyl 4-acetyl-5-(3-nitrophenyl)-1H-pyrrole-2,2(5H)-dicarboxylate: colorless oil; [α] D 20 =+249.2(c 0.3, CHCl 3 ); 1 H-NMR (CDCl 3, 400MHz) δ(ppm): 8.21(t, J=8.0Hz, 1H, ArH), 8.10-8.07(m, 1H, ArH), 7.69(d, J=7.6Hz, 1H, ArH), 7.45(t , J=8.0Hz, 1H, ArH), 6.82(d, J=2.0Hz, 1H, =CH), 5.52(d, J=1.6Hz, 1H, CH), 4.38-4.26(m, 4H, 2CH 2 ), 3.64(s, 1H, NH), 2.32(s, 3H, CH 3 ), 1.34 (q, J = 7.2Hz, 6H, 2CH 3 ); 13 C-NMR (CDCl 3 , 100MHz) δ (ppm): 194.0, 169.1, 169.0, 148.4, 147.2, 144.4, 13...

Embodiment 3

[0067] Adopt the method identical with embodiment 1, wherein: the aldehyde that adopts is 2-nitrobenzaldehyde, adds thin-layer chromatography silica gel H in common glass column, pressurized column chromatography with nitrogen (column length 15 centimetres, flow velocity 3 drop / second), the eluent was petroleum ether: ethyl acetate 6:1 (volume ratio), and the product 5ac was obtained with a yield of 87% and an ee of 90%.

[0068] Characterization data of compound 5ac:

[0069]

[0070] (R)-Diethyl 4-acetyl-5-(2-nitrophenyl)-1H-pyrrole-2,2(5H)-dicarboxylate: yellow oil; [α] D 20 =+364.4 (c 0.4, CHCl 3 ); 1 H-NMR (CDCl 3 , 400MHz) δ (ppm): 7.83 (dd, J 1 =8.0Hz,J 2 =1.2Hz, 1H, ArH), 7.50(dt, J 1 =8.2Hz,J 2 =1.2Hz, 1H, ArH), 7.39-7.33(m, 2H, ArH), 6.85(d, J=2.0Hz, 1H, =CH), 6.08(dd, J 1 =6.4Hz,J 2 =2.0Hz, 1H, CH), 4.38-4.20 (m, 4H, 2CH 2 ), 3.91(d, J=6.4Hz, 1H, NH), 2.31(s, 3H, CH 3 ), 1.33(t, J=7.2Hz, 3H, CH 3 ), 1.29(t, J=7.2Hz, 3H, CH 3 ); 13 C-NMR (CDCl 3 , ...

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Abstract

The invention discloses a novel compound chiral 2,2-diethoxy formyl-4-acyl-5-aryl or alkyl substituted 2,5-pyrroline with a following structure, a preparation method thereof and cytotoxic activity thereof on MCF7 mammary cancer cells. The chiral 2,5-pyrroline of the invention is a potential bioactive molecule skeleton and has certain cytotoxic activity on MCF7 mammary cancer cells, according to preliminary activity tests. The preparation method of the present invention comprises a series of asymmetric multiple ingredient reactions catalyzed by organic micromolecules and establishes a chiral 2,5-pyrroline ring structure from achiral raw materials through one step. The method has simple operations, mild reaction conditions and economical and easily available raw materials; and the 2,5-pyrroline derivative with a high optical purity (ee value reaching higher than 99%) is hopefully to be applied to fields of asymmetric syntheses and medical research and development.

Description

technical field [0001] The invention relates to a chiral 2,5-dihydropyrrole derivative and its synthesis method and biological activity, in particular to a 2,2-diethoxyformyl-4-acyl-5-aryl or alkyl The substituted 2,5-dihydropyrrole compound and its synthesis method and biological activity belong to the technical field of organic chemistry. Background technique [0002] 2,5-dihydropyrrole compounds have multiple biological activities, and many documents have publicly reported the biological activities of various 2,5-dihydropyrrole compounds, for example: Document Journal of Medicinal Chemistry 1998,41,3477 reported 2 , 5-dihydropyrrole derivatives can be used as antioxidants, which can provide cellular protection against various oxidative damages of mammalian cells; literature Journal of the American Chemical Society 2002, 124, 12135 and world patent WO 2006-US2582320060630 and other reports and It is disclosed that such compounds can selectively inhibit amine oxidase so as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/22C07D405/04C07D409/04C07D409/06C07B53/00A61K31/4025A61K31/40A61P35/00A61P15/14
Inventor 龚流柱石枫陶忠林
Owner UNIV OF SCI & TECH OF CHINA
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