Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Method for stereoselectively producing substituted polycyclic pyridone derivative

A compound and internal cyclization technology, which can be used in organic chemical methods, pharmaceutical formulations, organic active ingredients, etc., and can solve problems such as undisclosed pyrone compounds

Active Publication Date: 2020-07-07
SHIONOGI & CO LTD
View PDF7 Cites 20 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the examples disclosed in these documents are only directed to pyrone compounds having esters, amides or heterocycles at the α-position of the carbonyl group, but do not disclose pyrone compounds having hydrogen at the α-position of the carbonyl group

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
  • Method for stereoselectively producing substituted polycyclic pyridone derivative
  • Method for stereoselectively producing substituted polycyclic pyridone derivative
  • Method for stereoselectively producing substituted polycyclic pyridone derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0574]

[0575] step 1

[0576] To a suspension of NaH (3.96 g, 99 mmol) in DMF (36 mL) was added a solution of Boc-L-serine (9.27 g, 45 mmol) in DMF (45 mL) dropwise under ice-cooling under nitrogen atmosphere over 30 min, then Bromoacetaldehyde dimethyl acetal (10.6 mL, 90 mmol) was added dropwise over 10 minutes. The mixture was warmed to room temperature over 3 hours, and the mixture was stirred for 5 hours. The mixture was poured into water (90 g) and concentrated. Wash the aqueous layer with Et 2 O wash and the pH was adjusted to 3.3 by adding hydrochloric acid. The aqueous layer was extracted with ethyl acetate (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give crude compound 2 (9.52 g).

[0577] 1H-NMR (CDCl 3 )δ: 5.54-5.52 (br m, 1H), 4.50 (t, J=5.1Hz, 1H), 4.44-4.42 (br m, 1H), 4.01-3.99 (br m, 1H), 3.74 (dd, J = 9.7, 4.1 H...

Embodiment 2

[0602]

[0603] step 1

[0604] Add WSCD·HCl (288mg, 1.50 mmol), and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 12 (203 mg, 80% yield).

[0605] 1 H-NMR (CDCl 3 )δ: 7.90-7.79 (m, 4H), 7.35 (d, J = 7.7Hz, 1H), 6.20 (d, J = 7.7Hz, 1H), 5.81 (d, J = 13.3Hz, 1H), 5.41 ( d, J=3.5Hz, 1H), 5.07-5.01(m, 1H), 4.74(d, J=12.2Hz, 1H), 4.28-4.17(m, 3H), 3.90(dd, J=16.1, 7.1Hz , 1H), 3.40(t, J=10.8Hz, 1H), 1.80-1.68(m, 2H), 1.40-1.24(m, 6H), 0.83(t, J=6.9Hz, 3H).

[0606] step 2

[0607] To a mixture of compound 12 (51 mg, 0.10 mmol) and zinc powder (3.27 mg, 50 μmol) were added THF (0.5 mL) and 2-propanol (51 μL) under nitroge...

Embodiment 3

[0609]

[0610]Compound 13 (37.1 mg, 1.00 mmol) (which was synthesized in the same manner as described in Step 1 to Step 8 of Example 1) and 3-hydroxy-4-methylthiazole-2 (3H )-thione (22.1mg, 1.50mmol) in N-methylpyrrolidone (0.9mL) solution was added DABCO (44.9mg, 4.00mmol) and T3P (255mg, 4.00mmol), the mixture was stirred at room temperature for 2 hours, A solution of compound 14 was obtained. To the mixture was added t-nonanthiol (0.9 mL, 74 mmol) under nitrogen atmosphere, and the mixture was stirred at 55°C for 2 hours. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 15 (27 mg, 83% yield).

[0611] 1 H-NMR (DMSO) δ: 2.80-3.00 (m, 1H), 3.10-3.18 (m, 1H), 3.38-3.50 (m, 1H), 3.98-4.08 (m, 2H), 4.10-4.20 (m, 1H), 4.76-4.84(m, 1H), 5.04-5.14(m, 2H), 6.22(m, J=7.6Hz, 1H), 7.27-7.40(m, 4H), 7.56-7.60(m, 2H) , 7.70 (d, J=7.6Hz, 1H).

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 present invention provides a commercially applicable method for producing an intermediate of a substituted polycyclic pyridone derivative exhibiting cap-dependent endonuclease inhibitory activity.In the production method shown in the reaction formula (in the formula, the symbols are as defined in the description), by means of an intramolecular cyclisation reaction in which the stereochemistryof a compound shown in formula (III) or formula (VI) is controlled, a compound shown in formula (IV) and including an eliminable functional group on an asymmetric carbon is obtained, and said eliminable functional group is eliminated, whereby an optically active substituted 3-ring pyridone derivative shown in formula (VII) is highly enantioselectively obtained in a high yield.

Description

technical field [0001] The present invention relates to a process for the preparation of substituted polycyclic pyridone derivatives. In particular, the present invention relates to a stereoselective process for the preparation of substituted polycyclic pyridone derivatives and intermediates thereof. Background technique [0002] Known tricyclic pyridine derivatives such as 7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4] Azino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones as substituted polynucleotides with cap-dependent endonuclease inhibitory activity The core skeleton of cyclopyridone derivatives and serves as a common skeleton for other compounds useful as drugs such as those with HIV integrase inhibitory activity. Developments have been made to provide industrially favorable methods for synthesizing common scaffolds of such compounds for use as pharmaceuticals. [0003] Developments have also been made to provide efficient methods for the manufacture of pyrone compounds as...

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): C07D498/14C07D213/89C07D401/12
CPCC07D213/89C07D401/12C07D498/14C07D309/40C07D413/12C07C217/08Y02P20/55A61K31/5383C07B2200/13C07C215/10
Inventor 冈本和也上野达彦羽藤启夫箱木敏和马岛翔平
Owner SHIONOGI & CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com