A kind of chiral menthyl phenyl phosphonamide compound and its preparation method

A technology of hydroxyphenylphosphonamide and amine compounds, which is applied in the field of chiral menthylphenylphosphonamide compounds and their preparation, achieving obvious chiral induction and simple and easy-to-obtain effects

Active Publication Date: 2020-04-10
LIAOCHENG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But how to utilize Atherton-Todd reaction to prepare a kind of chiral menthyl phenyl phosphonamide compound has not been reported yet

Method used

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  • A kind of chiral menthyl phenyl phosphonamide compound and its preparation method
  • A kind of chiral menthyl phenyl phosphonamide compound and its preparation method
  • A kind of chiral menthyl phenyl phosphonamide compound and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] A chiral menthyl phenylphosphonamide compound 2a, comprising the following structural formula:

[0064]

[0065]A preparation method of chiral menthyl phenylphosphonamide compound 2a, comprising the steps of:

[0066] Preparation of pure R-menthylphenylphosphine hydrogen

[0067] a. Add menthol 0.17mol to 37% zinc chloride hydrochloric acid solution, stir at 35°C for 5 hours, return to room temperature, extract with 50mL of n-hexane, wash the organic phase with 30mL of water, and then wash with 10mL of concentrated sulfuric acid, water Wash with 30 mL, take the organic phase, dry with anhydrous magnesium sulfate, and remove the organic phase under reduced pressure to obtain a colorless oil;

[0068] b. Add 0.1 mol of magnesium, 0.1 mol of menthyl chloride and 50 mL of tetrahydrofuran in sequence in the three-necked flask to react for 6 hours to obtain the menthyl Grignard reagent;

[0069] c. Under the condition of an ice-water bath, add the prepared menthyl Grigna...

Embodiment 2

[0074] A chiral menthylphenylphosphonamide compound 2b, comprising the following structural formula:

[0075]

[0076] A preparation method of chiral menthyl phenylphosphonamide compound 2b, comprising the steps of:

[0077] The preparation of pure R-menthylphenylphosphine hydrogen is the same as in Example 1.

[0078] Preparation of Chiral Menthyl-Phenylphosphonamide Compound 2b

[0079] Add R-menthylphenylphosphine hydrogen (52.8mg, 0.2mmol), triethylamine (0.4mmol, 0.06mL) and carbon tetrachloride (2mmol) successively in the reaction flask, then add solvent acetonitrile (1mL), in n-Propylamine (0.2 mmol) was added at 0°C. The reaction was stirred for 30 minutes. Then warm to room temperature and stir overnight. Treat the reaction, add water (5mL) and ethyl acetate (5mL×3) to extract three times, dry over anhydrous magnesium sulfate, and vacuumize to obtain a crude product, then add petroleum ether (1mL) and dichloromethane (0.2mL) to weigh Crystallized to obtain 58....

Embodiment 3

[0081] A chiral menthyl phenylphosphonamide compound 2c, comprising the following structural formula:

[0082]

[0083] A preparation method of chiral menthyl phenylphosphonamide compound 2c, comprising the steps of:

[0084] The preparation of pure R-menthylphenylphosphine hydrogen is the same as in Example 1.

[0085] Preparation of chiral menthylphenylphosphonamides 2c

[0086] Add R-menthylphenylphosphine hydrogen (52.8mg, 0.2mmol), triethylamine (0.4mmol, 0.06mL) and carbon tetrachloride (2mmol) successively in the reaction flask, then add solvent acetonitrile (1mL), in n-Butylamine (0.2 mmol) was added at 0°C. The reaction was stirred for 30 minutes. Then warm to room temperature and stir overnight. Treat the reaction, add water (5mL) and ethyl acetate (5mL×3) to extract three times, dry over anhydrous magnesium sulfate, and vacuumize to obtain a crude product, then add petroleum ether (1mL) and dichloromethane (0.2mL) to weigh Crystallized to obtain 61.1 mg of p...

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Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a chiral menthyl phenylphosphonamide compound and a preparation method thereof. The chiral menthyl phenylphosphonamide compound has the following general formula (referring to the specification), wherein R1 is hydroxyl; R2 is hydroxyl, propyl, butyl, isopropyl, cyclopentyl, 2-chlorobenzyl, 2-methylidenefuran, 1-phenethyl or phenyl. The phosphonamide compound uses a phosphorus atom as a chiral source, has a more obvious chiral induction effect, and is more suitable for use in a chiral catalytic reaction; the phosphonamide compound has potentials of both drug activity and catalytic activity, and has development and application prospects; the phosphonamide compound is simple in synthesis method, easy to obtain and relatively good in application prospect.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a chiral menthyl phenylphosphonamide compound and a preparation method thereof. Background technique [0002] Phosphine compounds, including phosphinic peptides and phosphonamides, are widely used in medicine and biology. For example, optically pure phosphonamide derivatives have attracted extensive attention as matrix metalloproteinase inhibitors (MMs) in recent years. Among them, chiral phosphonamides show anti-cancer, anti-psoriasis and other drug activities. In addition, because the chiral phosphonamide of the phosphine chiral source has both the properties of a Lewis base and a Bronsted acid, the compound can be used as a chiral ligand and a small molecule catalyst to effectively catalyze asymmetric reduction and other reactions. [0003] The preparation of optically pure compounds of this type is quite challenging. Although some methods have been applied to th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/36C07F9/655C07F9/59A61P35/00A61P17/06B01J31/02
CPCB01J31/0268C07B2200/07C07F9/36C07F9/65515
Inventor 聂少振秦成成高丹迪丁婷婷
Owner LIAOCHENG UNIV
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