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Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof

A technology of tetrahydropyrrole and indole spirocycles, which is applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problems of limited substrate scope, limited methods, uneconomical and easy-to-obtain chiral raw materials, etc., and achieve operational Simple, mild reaction conditions, economical and easy-to-obtain raw materials

Inactive Publication Date: 2015-07-08
XUZHOU NORMAL UNIVERSITY
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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 tetrahydropyrrole-3,2′-oxindole spiro compounds are very limited, mainly through the formation of an optically pure proline and isatin-formed imine ylide and electron-poor 1,3-dipolar cycloaddition of alkenes (Tetrahedron Letters, 2008, 49, 2611) This method
However, this method uses optically pure starting materials to construct the chiral tetrahydropyrrole-3,2′-oxindole spiro ring skeleton, which has limitations such as uneconomical and easy availability of chiral raw materials, and a limited range of substrates.

Method used

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  • Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof
  • Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof
  • Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The (R)-type chiral phosphoric acid catalyst represented by 0.12mmol of N-methylisatin, 0.1mmol of 2-aminomalonate, 0.01mmol of formula 1, 100mg Molecular sieves (purchased from Tianjin Alpha Aisha Company) were put into a 10 mL glass reaction test tube, 0.5 mL of toluene was added, and stirred at room temperature for 15 minutes (600 rpm / min), then 0.5 mmol of dimethyl maleate and 0.5 mL of Toluene, react at 25°C for 36 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, wash the suction filter cake three times with 15 mL of ethyl acetate,...

Embodiment 2

[0062] Adopt the method identical with embodiment 1, wherein: the isatin that adopts is N-benzyl isatin, adds thin-layer chromatography silica gel H in common glass column, pressurizes column chromatography with nitrogen (column length 15 centimetres, flow velocity 3 drops / second), the eluent was petroleum ether: ethyl acetate 5:1 (volume ratio), and the product 5b was obtained with a yield of 88%, dr>99:1, ee 93%.

[0063] Characterization data of compound 5b:

[0064]

[0065] (2'S, 3'R, 4'S)-5', 5'-Diethyl3', 4'-dimethyl1-benzyl-2-oxospiro[indoline-3, 2'-pyrrolidine]-3', 4', 5′,5′-tetracarboxylate (5b): white solid; m.p.99-101℃; [α] D 20 =-44.3 (c 2.98, CHCl 3 ); 1 H-NMR (CDCl 3 , 400MHz) δ (ppm): 7.69 (dd, J 1 =7.6Hz,J 2 =0.9Hz, 1H, ArH), 7.31-7.22(m, 5H, ArH), 7.15(td, J 1 =7.8Hz,J 2 =1.2Hz, 1H, ArH), 6.99(td, J 1 =7.6Hz,J 2 =1.0Hz, 1H, ArH), 6.61(d, J=7.7Hz, 1H, ArH), 5.20(d, J=15.7Hz, 1H, CH), 4.56(d, J=8.1Hz, 1H, CH) , 4.51 (d, J=15.7Hz, 1H, CH), 4.44-4....

Embodiment 3

[0067] Adopt the method identical with embodiment 1, wherein: the isatin that adopts is N-phenyl isatin, adds thin-layer chromatography silica gel H in common glass column, pressurizes column chromatography with nitrogen (column length 15 centimetres, flow velocity 3 drops / second), the eluent is petroleum ether: ethyl acetate 5:1 (volume ratio), and the product 5c is obtained with a yield of 90%, dr>99:1, ee 80%.

[0068] Characterization data of compound 5c:

[0069]

[0070] (2'S, 3'R, 4'S)-5', 5'-Diethyl 3', 4'-dimethyl2-oxo-1-phenylspiro[indoline-3, 2'-pyrrolidine]-3', 4' , 5′,5′-tetracarboxyIate (5c): white solid; m.p.129-131℃; [α] D 20 =-67.3 (c 0.944, CHCl 3 ); 1 H-NMR (CDCl 3 , 400MHz) δ (ppm): 7.75 (dd, J 1 =7.6Hz,J 2 =0.9Hz, 1H, ArH), 7.54-7.47(m, 2H, ArH), 7.43-7.36(m, 3H, ArH), 7.21(td, J 1 =7.8Hz,J 2 =1.3Hz, 1H, ArH), 7.07(td, J 1 =7.6Hz,J 2 =1.0Hz, 1H, ArH), 6.72(d, J=7.7Hz, 1H, ArH), 4.60(d, J=8.1Hz, 1H, CH), 4.40-4.22(m, 4H, 2CH 2 ), 4.16 (d, J=8...

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Abstract

The invention relates to a spiro(pyrrolidine-3, 2'-oxindole)compound and especially relates to a chiral spiro(pyrrolidine-3, 2'-oxindole)compound and a synthesis method thereof and belongs to the technical field of organic chemistry. The synthesis method comprises that an electron deficient olefin (such as maleate, fumarate or acrylate) as philic1,3-dipole and ketimine obtained by an in-situ reaction of an isatin derivative and diethyl 2-aminomalonate undergo a 1,3-dipolar cycloaddition reaction in the presence of chiral phosphoric acid as a catalyst to produce the chiral spiro(pyrrolidine-3, 2'-oxindole)compound. The excess percentage (ee) of an enantiomer of the chiral spiro(pyrrolidine-3, 2'-oxindole)compound can reach to 80 to 89% and the ratio (dr) of a diastereoisomer of the chiral spiro(pyrrolidine-3, 2'-oxindole)compound can reach to 30: 1->99: 1. The chiral spiro(pyrrolidine-3, 2'-oxindole)compound has a potential for being used as a bioactive molecular scaffold. In addition, the chiral spiro(pyrrolidine-3, 2'-oxindole)compound has a certain cytotoxic activity for SW116 colorectal cancer cells.

Description

【Technical field】 [0001] The invention relates to a tetrahydropyrrole-3,2'-oxindole spiro compound, in particular to a chiral tetrahydropyrrole-3,2'-oxindole spiro compound and a synthesis method thereof, belonging to organic field of chemical technology. 【Background technique】 [0002] Tetrahydropyrrole-3,2'-oxindole spiro compounds have a variety of biological activities, and many documents have publicly reported the biological activities of various tetrahydropyrrole-3,2'-oxindole spiro compounds, such as: Document Eur.J.Med.Chem.2009,44,91 reports that this type of compound has antitumor activity; Document Eur.J.Med.Chem.2009,44,3272 reports that this type of compound has antidiabetic activity; Document Bioorg.Med.Chem.Lett.2010, 20, 7278; Eur.J.Med.Chem.2009, 44, 3821; J.Med.Chem.2008, 51, 5731; 45, 411, etc. reported that this type of compound has anti-mycobacterial activity; literature Bioorg.Med.Chem.2003, 11, 407; Bioorg.Med.Chem.Lett.2008, 18, 2342; Eur.J.Med.Chem...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/10A61P35/00
Inventor 石枫陶忠林屠树江
Owner XUZHOU NORMAL UNIVERSITY
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