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Asymmetric hydrogenation method of alpha-ketone amide compound

A compound and asymmetric technology, applied in the field of asymmetric catalysis, can solve the problems of reproducibility and economic efficiency, and achieve good industrial application prospects, high conversion rate and selectivity, and simple operation

Active Publication Date: 2018-09-18
SHENZHEN CATALYS SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many methods to obtain optically pure homophenylalanine and its derivatives, the reproducibility and economy of these methods still need to be improved

Method used

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  • Asymmetric hydrogenation method of alpha-ketone amide compound
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  • Asymmetric hydrogenation method of alpha-ketone amide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of 2a by hydrogenation of 1a

[0041]

[0042] In an argon-filled glove box, add the metal precursor [Ir(COD)Cl] to a 10 mL vial 2 (4.0mg, 5.9×10 -3 mmol), ligand L1 (7.3mg, 13.1×10 -3 mmol) and anhydrous i PrOH (3 mL). The mixture was stirred at 25 °C for 2 h to obtain an orange-red solution. The resulting solution (50 μL, c=4×10 -3 mmol / mL) and t BuOK at i The solution in PrOH (40 μL, c=0.05mmol / mL) was transferred to the i PrOH (2mL) solution in a 5mL vial. Transfer the vial to an autoclave and fill with 50 atm of H 2 , and stirred at room temperature for 12h. Hydrogen gas was slowly released in a well-ventilated fume hood. After the solution was concentrated, the metal complexes were removed through a silica gel column to obtain product 2a. According to nuclear magnetic analysis, the conversion rate was 99%, and through HPLC analysis, the measured ee value was 92%.

[0043] 1 H NMR (400MHz, CDCl 3 )δ7.39–7.34(m,2H),7.34–7.19(m,8H),6.75(s...

Embodiment 2

[0046] Preparation of 2a by hydrogenation of 1a

[0047] In an argon-filled glove box, add the metal precursor [Ir(COD)Cl] to a 10 mL vial 2 (4.0mg, 5.9×10 -3 mmol), ligand L2 (7.3mg, 13.1×10 -3 mmol) and anhydrous i PrOH (3 mL). The mixture was stirred at 25 °C for 2 h to obtain an orange-red solution. The resulting solution (50 μL, c=4×10 -3 mmol / mL) and t BuOK at i The solution in PrOH (40 μL, c=0.05mmol / mL) was transferred to the i PrOH (2mL) solution in a 5mL vial. Transfer the vial to an autoclave and fill with 50 atm of H 2 , and stirred at room temperature for 12h. Hydrogen gas was slowly released in a well-ventilated fume hood. After the solution was concentrated, the metal complexes were removed through a silica gel column to obtain product 2a. According to nuclear magnetic analysis, the conversion rate was 30%, and through HPLC analysis, the measured ee value was 81%.

[0048]

Embodiment 3

[0050] Preparation of 2a by hydrogenation of 1a

[0051] In an argon-filled glove box, add the metal precursor [Ir(COD)Cl] to a 10 mL vial 2 (4.0mg, 5.9×10 -3 mmol), ligand L3 (7.3mg, 13.1×10 -3 mmol) and anhydrous i PrOH (3 mL). The mixture was stirred at 25 °C for 2 h to obtain an orange-red solution. The resulting solution (50 μL, c=4×10 -3 mmol / mL) and t BuOK at i The solution in PrOH (40 μL, c=0.05mmol / mL) was transferred to the i PrOH (2mL) solution in a 5mL vial. Transfer the vial to an autoclave and fill with 50 atm of H 2 , and stirred at room temperature for 12h. Hydrogen gas was slowly released in a well-ventilated fume hood. After the solution was concentrated, the metal complexes were removed through a silica gel column to obtain product 2a. According to nuclear magnetic analysis, the conversion rate was 36%, and through HPLC analysis, the measured ee value was 84%.

[0052]

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PUM

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Abstract

The invention belongs to the field of asymmetric catalysis, and discloses an asymmetric hydrogenation method of an alpha-ketone amide compound. The asymmetric hydrogenation method comprises the following steps that under the existence of a catalyst, alkali and a solvent, an alpha-ketone-beta-alkene amide compound is subjected to reduction in the hydrogen atmosphere, and an alpha-hydroxyl-beta alkene amide compound is obtained; and the catalyst is obtained through complexing of metal iridium salt and a chiral ligand, and the chiral ligand is selected from the following compounds: (the formulasare shown in the description). The asymmetric hydrogenation method is easy to operate, high in conversion rate and selectivity and low in cost, has the advantages of being high in atom economy and environmentally friendly, and has a very good industrialized application prospect.

Description

technical field [0001] The invention belongs to the field of asymmetric catalysis, in particular to an asymmetric hydrogenation method of α-ketoamide compounds. Background technique [0002] Chiral homophenylalanine and its derivatives are important intermediates in organic synthesis. This structural unit exists in many chiral bioactive molecules, including ramipril, benazepril, Enalapril and other Pril drugs. Although there are many methods to obtain optically pure homophenylalanine and its derivatives, the reproducibility and economical efficiency of these methods still need to be improved. [0003] [0004] The inventors have designed a new synthetic route to prepare chiral homophenylalanine derivatives, as shown in the following formula, wherein asymmetric hydrogenation is a key step, and the hydrogenation substrate styryl glyoxylic acid derivatives can be obtained from aldol Obtained by condensation, the resulting chiral alcohol can be converted into an amino acid....

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C235/34C07D333/24C07D307/54C07C67/08C07C69/732
CPCC07B2200/07C07C51/06C07C51/353C07C51/363C07C67/08C07C231/02C07C231/12C07D307/54C07D333/24C07C235/34C07C69/732C07C235/78C07C59/84C07C59/88C07C59/90C07C59/48
Inventor 丁小兵王斯敏
Owner SHENZHEN CATALYS SCI & TECH CO LTD
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