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Method for synthesizing chiral gamma-aminophosphonate

An aminophosphonate and chiral technology, applied in the field of γ-aminophosphonate, to achieve the effects of wide substrate range, simple operation and simple raw materials

Active Publication Date: 2019-07-30
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above literatures are all about the 1,4-addition of phosphine nucleophiles to α, β-unsaturated carbonyl compounds, but the 1,4-addition of phosphine nucleophiles to α, β-unsaturated imines has not been reported

Method used

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  • Method for synthesizing chiral gamma-aminophosphonate
  • Method for synthesizing chiral gamma-aminophosphonate
  • Method for synthesizing chiral gamma-aminophosphonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-13

[0036] Embodiment 1-13 condition optimization

[0037] Add azadiene 1a (56.3 mg, 0.15 mmol), base (0.075 mmol), organocatalyst 5a (0.0075 mmol) and solvent (1.0-2.0 mL) to a 4 mL reaction vial at 20-30 °C , and then add diphenyl phosphite 2a (86.6 μl, 0.45 mmol) to the system, react at 30°C to -20°C for 4 hours to 7 days, add water after the reaction, extract with dichloromethane, and combine the two After the methyl chloride layer, dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the product compound 3aa was obtained by silica gel column chromatography. The reaction structure is as follows:

[0038]

[0039] The yield of the product is the isolated yield, the rr value is the ratio between the 1,4-addition product and the 1,2-addition product, and the ee value is the enantiomeric excess of the 1,4-addition product, see Table 1.

[0040] Table 1. Condition optimization for the synthesis of chiral γ-aminophosphonate 3aa a ...

Embodiment 2

[0043] Example 2: Synthesis of chiral γ-aminophosphonate 3

[0044] Add azadiene 1 (0.15 mmol), sodium carbonate (7.9 mg, 0.075 mmol), organocatalyst 5a (2.4 mg, 0.0075 mmol) and 1.0 mL of toluene to a 4 mL reaction flask at 20-30 °C , then the system was cooled to -20°C, and then phosphite 2 (0.45 mmol) was added to the system, reacted for 1-8 days at -20°C, water was added to the reaction system, extracted with dichloromethane, and the two After the methyl chloride layer, dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the product compound 3 was obtained by silica gel column chromatography. The reaction formula is as follows:

[0045] The yield of the product is the isolated yield, the rr value is the ratio between the 1,4-addition product and the 1,2-addition product, and the ee value is the enantiomeric excess of the 1,4-addition product, see Table 2 and Table 3.

[0046] Table 2. Synthesis of chiral γ-aminophosphonate ...

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Abstract

Provided is a method for synthesizing chiral gamma-aminophosphonates. Starting from azadiene and phosphite, reacting is conducted under the action of an inorganic base and an organic catalyst to obtain the chiral gamma-aminophosphonate containing various substituents. The method has simple and practical operation, high yield and high enantioselectivity.

Description

technical field [0001] The invention relates to gamma-aminophosphonate, in particular to a method for synthesizing chiral gamma-aminophosphonate with high enantioselectivity using an organic catalyst system. Background technique [0002] γ-Aminobutyric acid (GABA) is a four-carbon non-protein amino acid, which is an important free amino acid and widely exists in bacteria, plants and vertebrates. Has antihypertensive and antidepressant biological and pharmaceutical activities. Pregabalin, a derivative of GABA, has a good therapeutic effect on anxiety disorders. As analogs of γ-amino acid structure, γ-aminophosphonic acid derivatives also have important biological activities, for example, they can be used as inhibitors of goat brain glutamine synthetase and Escherichia coli glutamine synthetase. [0003] Optically active phosphonic acid derivatives are widely concerned by chemists because of their important applications in biology and medicine. Among many syntheses, enantio...

Claims

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Application Information

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IPC IPC(8): C07F9/655C07F9/6553
CPCC07B2200/07C07F9/65517C07F9/655354
Inventor 周永贵谷铮周吉孙蕾
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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