A kind of 2,2,5-trisubstituted 1,3,4 oxadiazole derivative and its synthesis method

A synthetic method, oxadiazole technology, applied in the field of organic synthesis, can solve the problems of harsh reaction conditions, lack of synthetic methods, poor functional group tolerance, etc., and achieve the effect of mild reaction conditions, good tolerance and wide application range

Active Publication Date: 2019-12-17
TAIYUAN UNIV OF TECH
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  • Abstract
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Problems solved by technology

A series of synthetic methods with certain uses have thus been developed (Synth.Commun.2014,44,1859.), but the synthetic methods currently reported usually have harsh reaction conditions (such as high temperature, strong acid, etc.), suitable reaction substrates Shortcomings such as narrow scope and poor functional group tolerance, meanwhile, most of the reported methods focus on the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives
2,2,5-trisubstituted 1,3,4-oxadiazole derivatives also have various important biological activities (Eur.J.Med.Chem.2013,68,394; Bioorg.Med.Chem.2011,19, 6292; 2009,19,332; 2008,16,7565; ActaPharmacol.Sin.2005,26,881.), but there is still a lack of effective synthetic methods for such compounds

Method used

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  • A kind of 2,2,5-trisubstituted 1,3,4 oxadiazole derivative and its synthesis method
  • A kind of 2,2,5-trisubstituted 1,3,4 oxadiazole derivative and its synthesis method
  • A kind of 2,2,5-trisubstituted 1,3,4 oxadiazole derivative and its synthesis method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthesis of 2,2,5-trisubstituted 1,3,4-oxadiazole derivatives, R in general structural formula I 1 = Ph, R 2 = Ph, R 3 = Ph, R 4 =OEt.

[0036]

[0037] In a 25mL schlenk bottle with a magnetic stirring bar, add 1.5mL dichloromethane, N-acyldiazaalkene (R 1 = Ph, R 2 =Ph) (84mg, 0.40mmol), and a-ketoester (R 3 = Ph, R 4 =OEt) (36mg, 0.2mmol), the resulting reaction mixture was placed at -78°C and stirred for 15 minutes, then 55μL (0.3mmol) of hexamethylphosphorous triamide diluted with 0.5mL of dichloromethane was added to a concentration of 0.6 mol / L, added dropwise to the above reaction mixture within 10 minutes, after the dropwise addition, the reaction was slowly warmed up to room temperature and stirred for 8 hours, after the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was chromatographed on a 200-300 mesh silica gel column The target compound of oxadiazole was obtained by purification, and the eluent was ...

Embodiment 2

[0041] Synthesis of 2,2,5-trisubstituted 1,3,4-oxadiazole derivatives, R in general structural formula I 1 = Ph, R 2 = 4-MeC 6 h 4 , R 3 = Ph, R 4 =OEt.

[0042]

[0043] The synthetic steps are basically the same as in Example 1, and the difference is listed as follows:

[0044] The N-acyldiazaolefin R used 1 = Ph, R 2 = 4-MeC 6 h 4 , the dosage was 90mg (0.4mmol), the reaction time at room temperature was 11 hours, and 60mg of the pure product in the form of light yellow oil was obtained, and the yield was 78%.

[0045] The data detection is as follows:

[0046] 1 H NMR (400MHz, C 6 D. 6 )δ7.94 (d, J=8.2Hz, 2H, ArH), 7.83 (dd, J=8.1, 1.5Hz, 2H, ArH), 7.49 (dd, J=8.8, 1.0Hz, 2H, ArH), 7.14 –7.03(m,5H,ArH),6.86(d,J=8.0Hz,2H,ArH),6.77(t,J=7.3Hz,1H,ArH),3.84(dq,J=10.7,7.1Hz,1H ,OCH 2 ), 3.72 (dq, J=10.7, 7.1Hz, 1H, OCH 2 ),1.95(s,3H,CH 3 ),0.60(t,J=7.1Hz,3H,OCH 2 CH 3 ); HRMS-ESI([M+H] + ) Calcd for C 24 h 23 N 2 o 3 387.1703, found 387.1705.

Embodiment 3

[0048] Synthesis of 2,2,5-trisubstituted 1,3,4-oxadiazole derivatives, R in general structural formula I 1 = Ph, R 2 =4-ClC 6 h 4 , R 3 = Ph, R 4 =OEt.

[0049]

[0050] The synthetic steps are basically the same as in Example 1, and the difference is listed as follows:

[0051] The N-acyldiazaolefin R used 1 = Ph, R 2 =4-ClC 6 h 4 , the dosage is 98 mg (0.4 mmol), the reaction solvent is tetrahydrofuran, the reaction mixture is stirred at -50 ° C for 10 minutes, and the reaction time at room temperature is 11 hours to obtain 49 mg of light yellow oily pure product with a yield of 60%.

[0052] The data detection is as follows:

[0053] 1 H NMR (400MHz, C 6 D. 6 )δ7.78(dd, J=8.1,1.5Hz,2H,ArH),7.64(d,J=8.8Hz,2H,ArH),7.44(dd,J=8.8,1.0Hz,2H,ArH),7.14 –7.04(m,5H,ArH),6.95(d,J=8.8Hz,2H,ArH),6.78(dt,J=8.4,1.0Hz,1H,ArH),3.83(dq,J=10.8,7.1Hz ,1H,OCH 2 ), 3.71 (dq, J=10.8, 7.1Hz, 1H, OCH 2 ),0.59(t,J=7.1Hz,3H,OCH 2 CH 3 ); HRMS-ESI([M+H] + ) Calcd for C 23 h 2...

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Abstract

The invention discloses a 2,2,5-tri-substituted 1,3,4-oxadiazole derivative and a synthetic method thereof and belongs to the technical field of organic synthesis. The synthetic method comprises the following steps: reacting N-acyl biazolefin and an alpha-dicarbonyl compound in presence of a three-coordinate phosphrus reagent, thereby obtaining the 2,2,5-tri-substituted 1,3,4-oxadiazole derivative. The synthetic method disclosed by the invention is mild in reaction conditions, wide in substrate application range and high in functional group tolerance; a synthetic technique for efficiently synthesizing the 2,2,5-tri-substituted 1,3,4-oxadiazole derivative with a novel structure is provided; and the invention provides a candidate compound for developing novel oxadiazole pharmaceutical molecules.

Description

technical field [0001] The invention relates to a 2,2,5-trisubstituted 1,3,4 oxadiazole derivative and a synthesis method thereof, belonging to the technical field of organic synthesis. Background technique [0002] 1,3,4-Oxadiazole derivatives have important and abundant biological activities, and are widely used in the fields of medicine and agriculture. Studies have shown that 1,3,4-oxadiazole compounds have good anti-inflammatory (Bioorg.Med.Chem.2005, 13, 4842.), anti-bacterial (Eur.J.Med.Chem.2010, 11, 4963; Bioorg.Med.Chem.Lett.2011,21,3536.), antifungal (IlFarmaco2002,57,171; Bioorg.Med.Chem.Lett.2011,21,444.), antispasmodic (Chem.Pharm.Bull.2008,56,509. ), analgesic (Eur.J.Med.Chem.2010,45,4587.), anti-cancer (Eur.J.Med.Chem.2012,54,855; 53,203; 48,192.), anti-tuberculosis (Bioorg.Med.Chem. 2005,13,4842; Eur.J.Med.Chem.2008,43,1989.), hypolipidemic (Eur.J.Med.Chem.2012,53,308.) and other activities. The widely used HIV integrase inhibitor Raltegravir (Nat.Rev.Dru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D271/107C07D413/04C07D498/10
CPCC07D271/107C07D413/04C07D498/10
Inventor 刘蓉芳周荣韩玲范彬彬李瑞丰
Owner TAIYUAN UNIV OF TECH
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