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Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation

A chemical reaction and chiral technology, applied in the field of chiral tridentate nitrogen phosphine ligands and its application in asymmetric hydrogenation reactions, can solve problems such as complex synthetic routes

Active Publication Date: 2015-12-16
SHENZHEN CATALYS SCI & TECH CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But in comparison, the synthetic route of SpiroPAP ligand is more complicated

Method used

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  • Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation
  • Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation
  • Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1L21

[0058] The synthesis of embodiment 1L21f-(S)-(R)-amphox

[0059]

[0060] N 2 A hexane solution of n-butyllithium (12.4mL, 1.4M) under protection was added dropwise to (3.6g, 14mmol) of (S)-1 in 20mL of anhydrous diethyl ether solution, keeping the temperature at 0°C and controlling Dropping time was 20 minutes. After the dropwise addition, the reaction solution was stirred at room temperature for 1.5 h, and then a solution of diphenylphosphine chloride (6.2 g, 28 mmol) in 10 mL of diethyl ether was slowly added dropwise. After the dropwise addition was completed, it was refluxed for 4h. Cool the reaction solution to room temperature, put it in an ice-water bath, slowly add a saturated aqueous solution of sodium bicarbonate dropwise, and extract the orange-yellow product with ether, combine the organic phases, wash with water, dry over anhydrous sodium sulfate, and dry in vacuo to obtain an orange oil liquid. After column purification and recrystallization from ethanol,...

Embodiment 2L25

[0072] The synthesis of embodiment 2L25 (R)-amphox

[0073]

[0074] N 2 CH under protection to 2-chloroethylamine hydrochloride (1 g, 8.62 mmol) 2 Cl 2 (20mL) solution was added Boc 2 O (2.07 g, 9.48 mmol) and triethylamine (1.56 mL, 11.2 mmol). After the reaction solution was stirred at room temperature for 24 h, TLC monitored the completion of the reaction and added water to separate the organic phase, and the water phase was separated with CH 2 Cl 2 Extracted three times with anhydrous Na 2 SO 4 After drying and filtration, the solvent was removed under reduced pressure. The target product 2 was purified by column chromatography as a yellow oil with a yield of 97%.

[0075]

[0076] 0°C, N 2 Ph 2 PH (18.6g, 100mmol) was slowly added dropwise into the anhydrous THF solution of t-BuOK (13.5g, 120mmol), after the dropwise addition was completed, it was raised to room temperature and stirred for 40min, then the raw material 2 was slowly added to the reaction so...

Embodiment 3

[0081] The synthesis of embodiment 3 (R)-amphox catalyst

[0082]

[0083] RuHCl(CO)(PPh 3 ) 3 (0.95g, 1mmol) and the ligand L25(R)-amphox (0.42g, 1.05mmol) were put into 7ml of anhydrous and oxygen-free 1,4-dioxane solvent, heated to reflux for 3h and then cooled to room temperature. Diethyl ether was added to the system and the temperature was lowered to -15°C to obtain crystals and filtered. The solid was washed twice with ether and then dried in vacuo to obtain a yellow solid with a yield of 88%, which indicated that the catalyst could be used for catalytic reactions without purification.

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Abstract

The invention discloses a chiral tridentate PNN ligand and application of the same in asymmetric hydrogenation and similar reactions. The tridentate nitrogen phosphine ligand disclosed in the invention has been the first reported nitrogen phosphine ligand containing chiral oxazoline so far and has been successfully applied to high-efficiency and high-selectivity hydrogenation and similar reactions of ketone and imine salts. Compared with other ligand, the ligand provided by the invention is simpler in synthetic route, higher in yield and environment-friendlier; moreover, the metal complex of the ligand shows better selectivity and a higher turn-over number in asymmetric hydrogenation. An iridium complex of the chiral tridentate PNN ligand has successfully realized asymmetric reduction of beta-ketone ester into beta-alcohol ester (which is a raw material for synthesis of molecular drugs duloxetine and atomoxetine), asymmetric hydrogenation of alpha-hydroxyacetophenone into alpha-hydroxyphenylethyl alcohol and asymmetric hydrogenation of acetophenone into phenylethyl alcohol, which is of important significance to production of the medical industry.

Description

technical field [0001] The invention relates to a chiral tridentate nitrogen phosphine ligand and its application in asymmetric hydrogenation reaction, which belongs to the field of fine chemical industry. Background technique [0002] Chiral compounds are widely used in pesticides, medicine, food, materials, fine chemicals and other fields, and are of great significance. With the improvement of living standards, people's demand for medicine and fine chemical products has greatly increased. In 2010, the global drug production value reached 880 billion US dollars, and generic drugs reached 103 billion US dollars. As the third largest pharmaceutical market in the world, China contains huge market opportunities. Therefore, scientists need to explore more efficient and environmentally friendly methods to design and selectively synthesize monochiral molecules. Asymmetric catalytic reaction is the most economical and efficient way to synthesize chiral compounds, and a large amo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/653B01J31/24C07F17/02C07B53/00C07D333/20C07D413/06C07D453/02C07D401/12C07D215/18C07C217/48C07C213/02C07D223/22C07D213/75C07D205/08C07F9/6558C07D401/14C07C67/31C07C69/732C07C69/734C07C29/143C07C33/26C07C33/46C07C33/20C07D333/16
Inventor 张绪穆
Owner SHENZHEN CATALYS SCI & TECH CO LTD
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