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Method for synthesizing phosphoramidon by utilizing hydrogen phosphorous acid diester intermediate

A hydrogen phosphite diester, a technology for synthesizing phosphoramidone, which is applied in the fields of peptide preparation, chemical instruments and methods, organic chemistry, etc. efficiency, the effect of simplifying the deprotection step

Inactive Publication Date: 2013-08-14
JIANGXI SCI & TECH NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this type of phosphoramidone analogs and precursors are very polar and difficult to purify

Method used

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  • Method for synthesizing phosphoramidon by utilizing hydrogen phosphorous acid diester intermediate

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Effect test

Embodiment 1

[0014] Embodiment 1: a method for synthesizing phosphoramidone by hydrogen phosphite diester intermediate, comprises the following steps:

[0015] Step 1: O-Benzyl-O-(α-L-2,3,4-triacetyl)-L-rhamnose-1-phosphorous diisopropylamine 4 Synthesis of : 580 mg (2.0 mmol, 1.0 equivalent) 2,3,4-triacetyl-α-L-rhamnose 2 and 0.51 ml (3.4 mmol, 1.7 equivalents) of dry DBU were dissolved in 10 ml of dry diethyl ether, and 820 mg (3.0 mmol, 1.5 equivalents) of benzyloxydiisopropylamidophosphorous acid was added dropwise under ice-bath conditions Acid chloride 3 5 ml of diethyl ether solution. The system gradually had a white precipitate, and the reaction was continued for 30 minutes after the dropwise addition was completed. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped twice with acetonitrile (5 ml) under reduced pressure. The residue was dissolved in ethyl acetate (5 ml), and the insoluble matter was filtered off. The filtrate was conce...

Embodiment 2

[0019] Embodiment 2: a method for synthesizing phosphoramidone by hydrogen phosphite diester intermediate, comprises the following steps:

[0020] Step 1: O-Benzyl-O-(α-2,3,4-triacetyl)-L-rhamnose-1-phosphoramidite 4 Synthesis of : 580 mg (2.0 mmol, 1.0 equivalent) 2,3,4-triacetyl-α-L-rhamnose 2 and 0.51 ml (3.4 mmol, 1.7 equiv.) of dry DBU were dissolved in 10 ml of dry tetrahydrofuran, and added dropwise at -20 °C in a solution of 820 mg (4.0 mmol, 2.0 equiv.) of benzyloxydiisopropylamino Phosphoryl chloride 3 5 ml of tetrahydrofuran solution. After the dropwise addition was completed, the reaction was continued for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped twice with acetonitrile (5 ml) under reduced pressure. The residue was dissolved in ethyl acetate (5 ml), and the insoluble matter was filtered off. The filtrate was concentrated to give a light yellow oily phosphoramidite intermediate 4 The crude produ...

Embodiment 3

[0024] Embodiment 3: a method for synthesizing phosphoramidone by hydrogen phosphite diester intermediate, comprises the following steps:

[0025] Step 1: O-Benzyl-O-(α-2,3,4-triacetyl)-L-rhamnose-1-phosphoramidite 4 Synthesis of : 1.16 g (4.0 mmol, 1.0 equivalent) of 2,3,4-triacetyl-α-L-rhamnose 2 and 1.2 ml (4.0 mmol, 2.0 equivalents) of dry DBU were dissolved in 20 ml of dry diethyl ether, and at -20 °C, 1.64 g (8.0 mmol, 2.0 equivalents) of benzyloxydiisopropylamino was added dropwise Phosphoryl chloride 3 10 ml of diethyl ether solution. After the dropwise addition was completed, the reaction was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped twice with acetonitrile (5 ml) under reduced pressure. The residue was dissolved in ethyl acetate (5 ml), and the insoluble matter was filtered off. The filtrate was concentrated to give a light yellow oily phosphoramidite intermediate 4 The crude product was ...

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Abstract

The invention relates to a method for synthesizing phosphoramidon by utilizing a hydrogen phosphorous acid diester intermediate. The method comprises the following steps of: generating a phosphoramidite intermediate under the alkaline condition by utilizing alpha-L-triacetyl rhamnose and benzyloxy-diisopropyl amino phosphorus oxychloride; carrying out catalytic hydrolysis with weak acid to obtain alpha-L-rhamnose-1-hydrogen phosphorous acid diester intermediate; reacting with a nitrogen terminal of leucine-tryptophan dipeptide benzyl ester by utilizing an oxidation coupling method to obtain a phosphamide precursor; and finally carrying out 'one-pot' hydrogenation and deacetylation to remove all the protecting groups of the phosphamide precursor, and carrying out chromatographic purification by virtue of glucose gel to obtain high-purity phosphoramidon. According to the method, the protecting groups of three synthesis fragments, namely L-rhamnose, phosphorylation reagent and leucine-tryptophan dipeptide, are designed and optimized, so that a step of removing protection of a product precursor is simplified to the utmost extent; and yield of a target product is greatly increased by utilizing a novel hydrogen phosphorous acid diester intermediate and the oxidation coupling method, so that a new method is established for chemical synthesis of phosphoramidon.

Description

technical field [0001] The invention belongs to the technical field of chemical preparation of natural product biochemical reagents, and relates to a method for synthesizing phosphoramidone through a hydrogen phosphite diester intermediate. Background technique [0002] Phosphoramidon--Phosphoramidon (also known as phosphoryl dipeptide) was first obtained from Streptomyces ( Streptomyces tanashiensis ) is a phosphorus-containing natural glycopeptide compound isolated from the culture medium. Phosmimethone can form a very strong bond at the active site of Thermolysin, and has a very strong inhibitory effect on Thermolysin. Thermolysin and its family of metalloproteinases (Thermolysin-like proteinases, TLPs) have good thermal stability and protein cleavage activity, and are widely used in biochemistry, molecular biology, genetics, immunology, oncology, cell engineering and many other frontier fields of biology and medicine. For example, thermolysin is used for protein seque...

Claims

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Application Information

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IPC IPC(8): C07K9/00C07K1/16C07K1/06
CPCY02P20/55
Inventor 孙麒龚珊珊杨庆昆蒲守智刘国栋多树旺肖强
Owner JIANGXI SCI & TECH NORMAL UNIV
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