3-difluoroalkyl substituted amino oxindole derivative and synthesis method thereof

A technology of carbooxindole derivatives and substituents, applied in the field of aminoquaternary carbooxindole derivatives and their synthesis, achieving high yield, simple raw materials and wide application range

Inactive Publication Date: 2015-12-09
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is still no report on the skeleton of 3-aminoquaternary carbooxindole derivatives containing C3-difluoroalkyl substitution. In comparison, the synthesis of such compounds is more challenging

Method used

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  • 3-difluoroalkyl substituted amino oxindole derivative and synthesis method thereof
  • 3-difluoroalkyl substituted amino oxindole derivative and synthesis method thereof
  • 3-difluoroalkyl substituted amino oxindole derivative and synthesis method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] Under nitrogen, add Ph to the 25.0mL Schleck reaction flask 3 PAuCl (3.7mg, 0.0075mmol) and AgOTf (1.9mg, 0.0075mmol) were added, followed by anhydrous dichloromethane (5.0mL), and the reaction solution was stirred at room temperature for half an hour. join in turn Molecular sieve, indoimine I-1 (0.25mmol), difluoroenol silyl ether II-1 (2.5mmol), TLC detection raw materials have basically been reacted, stop the reaction. Direct column chromatography, eluent (CH 2 Cl 2 / EtOAc=50:1~30:1), the product III-1 was obtained as a white solid with a yield of 92%. 1 HNMR (400MHz, CDCl 3 ):δ7.82-7.80(m,2H),7.60-7.56(m,1H),7.42-7.33(m,4H),7.03-7.00(m,1H),6.84-6.82(m,1H),6.18 (s,1H),3.21(s,3H),1.27(s,9H); 19 FNMR (376MHz, CDCl 3 ): δ-107.17(d, J=275Hz, 1F), -108.29(d, J=275Hz, 1F), -119.81(s, 1F); 13 CNMR (100MHz, CDCl 3): δ188.73(t, J=28Hz), 170.73, 153.24, 144.85, 134.43, 132.70, 130.46, 129.94(t, J=3.6Hz), 128.41, 125.08, 123.71, 122.75, 115.32(t, J=265Hz ...

Embodiment 2

[0039]

[0040] Under nitrogen, add AgOTf (1.9 mg, 0.0075 mmol), and anhydrous dichloromethane (3.0 mL) to a 25.0 mL Schleck reaction flask, followed by Molecular sieve, indimine I-2 (0.25mmol), difluoroenol silyl ether II-1 (0.5mmol), TLC detection raw materials have basically been reacted, stop the reaction. Direct column chromatography, eluent (CH 2 Cl 2 / EtOAc=50:1~30:1), the product III-2 was obtained as a white solid with a yield of 80%. 1 HNMR (400MHz, CDCl 3 ):δ7.87-7.85(m,2H),7.63-7.59(m,1H),7.45-7.42(m,2H),7.17-7.14(m,1H),7.08-7.03(m,1H),6.79 -6.76(m,1H),6.21(s,1H),3.22(s,3H),1.31(s,9H); 19 FNMR (376MHz, CDCl 3 ): δ-106.52(d, J=279Hz, 1F), -108.11(d, J=279Hz, 1F), -119.81(s, 1F); 13 CNMR (100MHz, CDCl 3 ), 128.57, 125.33(d, J=7.2Hz), 116.71(d, J=23.4Hz), 115.20(t, J=266Hz), 113.47(d, J=25.6Hz), 108.94(d, J=7.9Hz) ,81.22,65.34(t,J=22.9Hz),28.00,26.83.MS(EI):434(M + ,6),334(3),205(3),179(100),105(15),77(15),57(10),44(5).HRMS(EI):ExactmasscalcdforC 22 h ...

Embodiment 3

[0042]

[0043] Add Hg(OTf) to a 25.0mL Schleck reaction flask under nitrogen 2 (0.0075mmol), and anhydrous dichloroethane (3.0mL), followed by adding Molecular sieve, indoimine I-3 (0.25mmol), difluoroenol silyl ether II-1 (0.75mmol), TLC detection raw materials have basically been reacted, stop the reaction. Direct column chromatography, eluent (CH 2 Cl 2 / EtOAc=50:1~30:1), the product III-3 was obtained as a white solid with a yield of 70%. 1 HNMR (400MHz, CDCl 3 ):δ7.87-7.85(m,2H),7.63-7.59(m,1H),7.46-7.42(m,2H),7.36-7.31(m,2H),6.79-6.76(m,1H),6.19 (s,1H),3.22(s,3H),1.31(s,9H); 19 FNMR (376MHz, CDCl 3 ): δ-106.38(d, J=280Hz, 1F), -107.87(d, J=280Hz, 1F); 13 CNMR (100MHz, CDCl 3 ): δ188.20(t, J=28Hz), 170.44, 153.24, 143.57, 134.75, 132.36, 130.36, 130.06(t, J=4Hz), 128.58, 128.15, 125.55, 125.48, 115.22(t, J=266Hz) ,109.35,81.29,65.09(t,J=23Hz),28.02,26.83.MS(EI):452[M( 37 Cl) + ,2.6],450[M( 35 Cl) + ,7.7],350(3),221(3),195(100),197(33),105(20),77(20),57(1...

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Abstract

The present invention discloses an AG-041R difluoro analog, a 3-difluoroalkyl substituted 3-amino quaternary carbon oxindole derivative and a synthesis method thereof, wherein the compound has a structure represented by the following formula, has potential biological activity and efficacy, provides powerful technical support for development of new drugs, and has high practical values. The synthesis process of the compound comprises: adding a catalyst to a reaction container, sequentially adding isatin imine, a solvent and a nucleophilic reagent difluoro silyl enol ether, stirring at a temperature of -78 DEG C -100 DEG C until the TLC display reaction is completed, and separating through column chromatography to obtain the product. According to the present invention, the synthesis method has characteristics of simple and easily-available raw materials, mild reaction condition, simple operation and wide substrate application range, and the compounds CF2-AG-041R and 3-difluoroalkyl substituted amino oxindole have potential and important medicinal values.

Description

technical field [0001] The invention belongs to the technical field of organic compounds, and relates to drug molecule AG-041R difluoro analogs and 3-difluoroalkyl substituted aminoquaternary carbooxindole derivatives and their synthesis methods. Background technique [0002] The drug molecule AG-041R is a gastrin and Cholecyclokinin-B receptor antagonist, and is a very effective drug for repairing cartilage defects. Its structure is shown in formula (1): [0003] [0004] Fluorine atoms have special properties such as the largest electronegativity and smaller atomic radius. Therefore, selectively introducing fluorine atoms or fluoroalkyl groups into organic compounds is an important means to change the physical, chemical and biological activities of compounds in pharmaceutical research. In particular, many research results have shown that the introduction of difluoroalkyl substituents in bioactive molecules can often significantly enhance their metabolic stability, bio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/40
CPCY02P20/55C07D209/40
Inventor 周剑余金生
Owner EAST CHINA NORMAL UNIV
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