Chiral 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof

A technology of indole derivatives and synthetic methods, applied in the field of new chiral 3, can solve the problems of complex synthesis of raw materials, many reaction steps, and low yield

Active Publication Date: 2015-06-10
广东和博制药有限公司
View PDF2 Cites 14 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many of these routes and synthetic methods have disadvantages such as complex synthesis of raw materials, many reaction steps, long reaction time, high cost, low yield, cumbersome operation and post-treatment, etc., and their practical and economic value are greatly limited.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Chiral 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof
  • Chiral 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof
  • Chiral 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]

[0050] Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in dichloromethane (1.5m1) at 25°C; A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in methane (1.5ml) was added dropwise to the reaction at 25°C over 1h. In the system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30~1:10) to obtain a pure product. The yield was 72%, the dr value was greater than 95:5, and the ee value was 86%.

[0051] 1 H NMR (400MHz, CDCl 3 )δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14 (m, 3H) , 7.12-7.08(m, 1H), 7.05(s, 1H), 7.03-6.99(m, 3H), 6.78-6....

Embodiment 2

[0053]

[0054] Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.33mmol, 1.1eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in toluene (1.5ml) at 25°C; then, dissolved in toluene (1.5ml) A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) was added dropwise to the reaction system within 1h at 25°C. After completion, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30~1:10) to obtain a pure product. The yield was 80%, the dr value was greater than 95:5, and the ee value was 86%.

[0055] 1 H NMR (400MHz, CDCl 3 )δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14 (m, 3H) , 7.12-7.08(m, 1H), 7.05(s, 1H), 7.03-6.99(m, 3H), 6.78-6.75(m, 3H), 5.38(d, J=1...

Embodiment 3

[0057]

[0058] Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and 3,5-difluorophenyl substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in toluene (1.5ml) was added dropwise to the reaction at 25°C over 1h. In the system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30~1:10) to obtain a pure product. The yield was 75%, the dr value was greater than 95:5, and the ee value was 92%.

[0059] 1 H NMR (400MHz, CDCl 3 )δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14 (m, 3H) , 7.12-7.08(m, 1H), 7.05(s, 1H), 7.03-6.99(m, 3H), 6.78-6.75(m, ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a chemical synthetic method of a novel chiral 3,3-disubstituted oxoindole derivative with PTP1B inhibiting action. With diazoisatin, indole, arylamine and aldehyde ester as raw materials, a metal catalyst as catalyst, chiral phosphoric acid as a co-catalyst, an organic solvent as a solvent, and molecular sieve shown in the specification as an additive, a one-step reaction is performed under the condition of 25 degrees centigrade, and the product undergoes column chromatography purification to obtain the target product. The synthetic method has the advantages of high step economy, strong atom economy, high diastereoselectivity and enantioselectivity, high yield, mild reaction condition, and simple and safe operation. The optically pure chiral 3,3-disubstituted oxoindole derivative with two chiral centers synthesized in the invention is an important intermediate in chemical engineering, chemistry and medicines, and has a wide application prospect in the fields of medicines and the chemical engineering.

Description

technical field [0001] The invention relates to a novel chiral 3,3-disubstituted oxindole derivative and its synthesis method and application, belonging to the field of preparation and application of pharmaceutical intermediates. Background technique [0002] Chiral 3,3-disubstituted oxindole derivatives are a class of important skeleton structural units for the construction of natural products and synthetic drugs, and many natural product structures contain such skeleton structures. Cyclotryptamine widely has a 3,3-disubstituted oxindole skeleton structure. For example, the natural compound (+)-WIN 64821 isolated from Aspergillus is a potential SP receptor antagonist of neurokinin (NK-1) receptor and cholecystokinin B (cholecystokinin B) receptor (J Antibiot., 1994, 47, 411; J. Antibiot., 1994, 47, 399; J. Antibiot., 1994, 47, 391). Chaetocin not only has good antibacterial and cell growth inhibitory activity, but also is a potential histone lysine-specific methyltransfer...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34A61P3/04A61P3/10
CPCC07D209/34
Inventor 胡文浩荆常诚肖国兰邢栋
Owner 广东和博制药有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap