Bifluoro C2-spirindoline compound and preparing method thereof

A compound, difluorinated technology, applied in the field of medicine and chemical industry, to achieve the effect of excellent yield, good compatibility, cheap and easy-to-obtain raw materials

Active Publication Date: 2018-09-28
GUANGZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] These natural products and drugs usually have multiple chiral centers in their molecular skeletons, including all-carbon quaternary carbons and heteroquaternary carbons substituted by heteroatoms such as O and N, which are quite challenging in synthesis.

Method used

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  • Bifluoro C2-spirindoline compound and preparing method thereof
  • Bifluoro C2-spirindoline compound and preparing method thereof
  • Bifluoro C2-spirindoline compound and preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The synthesis of difluoro C2-spiro ring indoline compound shown in formula I-1, reaction formula is as follows:

[0027]

[0028] Add 3,3-difluoro-2-(phenylethynyl)-3H-indole II-1 (57.0mg, 0.225mmol) and benzo[d]thiazol-2-amine II-1 in sequence in a 5mL reaction flask (22.5mg, 0.15mmol), catalyst 1,5,7-triazidebicyclo(4.4.0)dec-5-ene (TBD, 10.5mg, 0.075mmol) and ethyl acetate (1.0mL), the reaction solution Stir at room temperature for 5h. TLC detects that the raw materials have basically reacted, and the reaction is stopped. The reaction solution was subjected to direct column chromatography, eluent (ethyl acetate / dichloromethane=1 / 10), to obtain product I-1 (50.7 mg) in the form of yellow foam, with a yield of 84%.

[0029] The analytical data of difluoro C2-spirocyclic indoline compound shown in formula I-1: 1 H NMR (500MHz, CDCl 3 ):δ4.52(s,1H),5.28(d,J=5Hz,1H),5.89(d,J=10Hz,1H),6.74(d,J=5Hz,1H),6.83(t,J =10Hz,1H),6.93(t,J=5Hz,1H),7.01(t,J=5Hz,1H), 7.31-7.34(...

Embodiment 2

[0031] The synthesis of difluorinated C2 spiroindoline compound shown in formula I-2, reaction formula is as follows:

[0032]

[0033] Add 5-methoxy-3,3-difluoro-2-(p-phenylethynyl)-3H-indole II-2 (63.6mg, 0.225mmol), benzo[d]thiazole in sequence in a 5mL reaction flask -2-Amine III-1 (22.5mg, 0.15mmol), catalyst triethylamine (3.1mg, 0.03mmol) and acetonitrile (2.0mL), the reaction solution was stirred at room temperature for 5h. TLC detects that the raw materials have basically reacted, and the reaction is stopped. The reaction solution was subjected to direct column chromatography, eluent (ethyl acetate / dichloromethane = 1 / 11), to obtain product I-2 (56.5 mg) in the form of yellow foam, with a yield of 87%.

[0034] The analytical data of difluorinated C2 spiroindoline compound shown in formula I-2: 1 H NMR (500MHz, CDCl 3 ):δ3.73(s,3H),4.51(s,1H),5.22(d,J=2.4Hz,1H); 5.77(d,J=10Hz,1H), 6.39(dd,J=10,5.0 Hz,1H),6.73(d,J=10Hz,1H),6.89(d,J=2.6Hz,1H),6.92(t,J=10Hz,1H),7.32...

Embodiment 3

[0036] The synthesis of difluoro C2-spiro ring indoline compound shown in formula I-3, reaction formula is as follows:

[0037]

[0038] Add 3,3-difluoro-2-(p-phenylethynyl)-3H-indole II-3 (61.0 mg, 0.225 mmol), benzo[d]thiazol-2-amine III- 1 (22.5mg, 0.15mmol), catalyst pentamethylpiperidine (PMP, 17.9mg, 0.045mmol) and toluene (5.0mL), the reaction solution was stirred at room temperature for 5h. TLC detected that the raw material had basically reacted, and the reaction was stopped. The reaction solution was subjected to direct column chromatography, eluent (ethyl acetate / dichloromethane=1 / 12), to obtain the product I-3 (45.5 mg) as a yellow solid, with a yield of 72%.

[0039] The analytical data of difluorinated C2 spiroindoline compound shown in formula I-3: 1 H NMR (500MHz, CDCl 3 ): δ4.51(s,1H),5.25(d,J=1.9Hz,1H),5.92(d,J=5Hz,1H),6.74(d,J=10Hz,1H),6.87(td,J =10,1.5Hz,1H),6.93(t,J=10Hz,1H),7.03(t,J=10Hz,1H),7.10-7.19(m,2H),7.31-7.35(m,4H),7.49 (d,J=10Hz,1H); 13 ...

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Abstract

The invention discloses a bifluoro C2-spirindoline compound belonging to a series of novel compounds. The bifluoro C2-spirindoline compound has good antiviral activity and is expected to become a novel antiviral medicine. The invention further discloses a preparing method of the indoline compound. The compound has the advantages that catalysts and raw materials adopted in the preparing method arelow in price and easy to obtain; reaction conditions are mind, and operation is convenient; the substrate range is wide, the compatibility of functional groups is high, and the good and even excellentyield can be obtained for a series of bifluoro C2-spirindoline products.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a difluoro C2-spirocyclic indoline compound and a preparation method thereof. Background technique [0002] C2-spiro indoline is an important class of structural units that widely exist in natural products and drug molecules. Some representative natural products containing C2-spiro indoline structural units are shown below. Studies have shown that compounds containing the core skeleton of C2-spirocyclic indoline usually have better biological activity. For example, plant alkaloids ((±)-erucalexin) showed good antifungal activity against R. solani and S. sclerotiorum, two important pathogens of cruciferous oilseeds; Demonstrates good opioid agonist activity in the mouse vas deferens and guinea pig ileum. In addition, taking advantage of the light- and pH-sensitive characteristics of C2-spiropyran, spiropyran has been widely used in the fields of optical switches, ph...

Claims

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Application Information

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IPC IPC(8): C07D513/20
CPCC07D513/20
Inventor 刘运林林晓彤毛翔宇陈国术
Owner GUANGZHOU UNIVERSITY
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