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Oxaspiro compound and efficient synthesis and splitting method thereof

A ring compound, oxaspiro technology, applied in the field of a new type of oxaspiro compound and its synthesis and resolution, can solve the problem of insufficient number of spiro ring skeleton ligands, difficulty in spiro ring skeleton synthesis, limited modification, etc. question

Active Publication Date: 2019-08-16
SHENZHEN CATALYS SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compared with the development of axial chiral ligands, spirocyclic skeleton ligands are not only insufficient in number but also in application. One of the important reasons is that the synthesis of spirocyclic skeletons is relatively difficult, and the modification is only limited. limited to the existing skeleton

Method used

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  • Oxaspiro compound and efficient synthesis and splitting method thereof
  • Oxaspiro compound and efficient synthesis and splitting method thereof
  • Oxaspiro compound and efficient synthesis and splitting method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of compound 6:

[0032]

[0033] 1,3-Difluorobenzene (35g, 306mmol) was dissolved in 150mL of anhydrous tetrahydrofuran, under Ar protection, at -78°C, n-butyllithium (123mL, 2.5M n-hexane solution) was added dropwise, and the addition was completed After that, it was stirred at -78°C for 1 h, and then methyl trimethylsiliconate (24.339 g, 150 mmol) was added slowly. After the addition was complete, the reaction was warmed to -30°C and stirred for a while and then warmed to room temperature. After the reaction was completed, dilute hydrochloric acid was added at low temperature to quench the reaction, and at the same time, the trimethylsilyl group was removed. The reaction mixture was extracted with ether and dichloromethane, and the organic phases were combined. The solvent was removed under reduced pressure to obtain the target product 1, which was directly subjected to the next reaction without purification.

[0034]

[0035] Compound 1 and 150 mL ...

Embodiment 2

[0050] Resolution of compound 6:

[0051]

[0052] In a 1000mL reaction flask, add rac-6 (51.2g, 200mmol), D-proline (11.5g, 100mmol), and then add 300mL ethyl acetate. The reaction mixture was stirred at reflux for 10 h. A large amount of white solids were precipitated, cooled to room temperature and filtered and collected white solid A; the mother liquor after filtration was desolvated under reduced pressure, and then D-proline (11.5g, 100mmol) was added again, the solvent was changed to acetonitrile, and the same under reflux conditions Under stirring for 10h, a large number of white solids were precipitated and cooled to room temperature. The white insoluble matter B was collected by filtration. The solvent was removed from the mother liquor under reduced pressure, and then the above resolution process was repeated. All the collected solid A was added to a mixed solvent of ethyl acetate and water for shaking, and the white insoluble matter gradually dissolved and dis...

Embodiment 3

[0054] Synthesis of oxaspirocyclic diamines:

[0055]

[0056] N 2 To a 250 mL reaction flask was added (S)-6 (7.68 g, 30 mmol) followed by 150 mL of dry dichloromethane under atmosphere. Pyridine (6.0 mL, 100 mmol) was added under stirring at room temperature. After the reaction system was clarified, it was cooled to zero, and then Tf was added dropwise. 2 O (12.0mL, 70mmol), after the dropwise addition was completed, it was raised to room temperature and stirred for 1h. Water was added to quench the reaction. The reaction system was washed with dilute hydrochloric acid, the organic phase was desolvated under reduced pressure, and the product (S)-7 (15.6g, yield: 99%) could be obtained through column chromatography

[0057] 1 H NMR (500MHz, CDCl 3 )δ4.70 (d, J=10.0Hz, 2H, CH 2 ),4.87-4.90(m,2H,CH 2 ), 6.91-6.93 (m, 4H, Ar), 7.32 (dd, J 1 =8.5Hz,J 2 =8.0Hz,2H,Ar).

[0058]

[0059] N 2 Under atmosphere, add (S)-7 (2.60g, 4mmol), Pd(OAc) into the reaction tube...

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Abstract

The invention belongs to the technical field of chemical synthesis, relates to synthesis and splitting of a class of novel oxaspiro compounds, and particularly provides a method for efficiently synthesizing an oxaspiro compound, wherein a reaction route is properly optimized, a spiro-difluoro intermediate can be efficiently obtained only through four steps after the optimizing, the operation of the synthesizing method is simple, the further scale-up is easily performed, and oxaspiro diphenol can be efficiently split with a cheap and readily available splitting reagent.

Description

technical field [0001] The invention relates to a novel oxaspiro compound and its synthesis and resolution. The compound can be used as a skeleton structure of a chiral ligand, has high potential application value in the field of asymmetric catalysis, and belongs to the field of asymmetric catalysis. Background technique [0002] The research on the catalytic performance of chiral spiro ligands began in 1992. Kumar et al. successfully applied the optically pure cis,cis-spiro[4,4]-1,6-nonanediol-modified lithium aluminum hydride to The asymmetric reduction of ketones has achieved excellent enantioselectivity (up to 98% ee). In 1996, Keay et al. successfully applied the same chiral diol as a chiral prosthetic group to modify acryloyl chloride in the asymmetric Diels-Alder reaction of cyclopentadiene. Subsequently, Chen Xinzi and Jiang Yaozhong designed and synthesized different types of bidentate phosphite ligands based on this framework, and discussed their application in r...

Claims

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Application Information

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IPC IPC(8): C07D493/10C07F9/6571C07B53/00B01J31/22C07C231/12C07C233/07
CPCB01J31/1845B01J31/2213B01J2231/645B01J2531/822C07B53/00C07B2200/07C07C231/12C07D493/10C07F9/657154C07C233/07
Inventor 张绪穆陈根强赵凌宇陈奇姝
Owner SHENZHEN CATALYS SCI & TECH CO LTD
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