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The method for synthesizing phosphoramidone by hydrogen phosphite diester intermediate

A technology for the synthesis of hydrophosphite diester and phosphoramidone, which is applied in the production of peptides and bulk chemicals, can solve the problems of high polarity of precursors and difficult purification, and achieves improved yield and simplified deprotection. The effect of the steps

Inactive Publication Date: 2016-04-06
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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  • The method for synthesizing phosphoramidone by hydrogen phosphite diester intermediate

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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: 580mg (2.0mmol, 1.0 equivalent) 2,3,4-triacetyl-α-L-rhamnose 2 and 0.51ml (3.4mmol, 1.7 equivalent) of dry DBU were dissolved in 10ml of dry ether, and a solution of 820mg (3.0mmol, 1.5 equivalent) of benzyloxydiisopropylaminophosphorous acid chloride was added dropwise under ice-bath conditions 3 5ml of 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 concentrated to give a l...

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: 580mg (2.0mmol, 1.0 equivalent) 2,3,4-triacetyl-α-L-rhamnose 2 and 0.51ml (3.4mmol, 1.7eq) of dry DBU were dissolved in 10ml of dry tetrahydrofuran, and 820mg (4.0mmol, 2.0eq) of benzyloxydiisopropylamidophosphorous acid was added dropwise at -20°C Acid chloride 3 5ml 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 product was directly used in...

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 The synthesis of: 1.16g (4.0mmol, 1.0 equivalent) 2,3,4-triacetyl-α-L-rhamnose 2 and 1.2ml (4.0mmol, 2.0eq) of dry DBU were dissolved in 20ml of dry diethyl ether, and 1.64g (8.0mmol, 2.0eq) of benzyloxydiisopropylaminoimide was added dropwise at -20°C Phosphorus oxychloride 3 10ml 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 directly used in the n...

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Abstract

A method for synthesizing phosphoramidone through a hydrogen phosphite diester intermediate, comprising the steps of: utilizing α-L-triacetylrhamnose, and benzyloxy diisopropylaminophosphorous acid chloride is generated under alkaline conditions Phosphoramidite intermediate; weakly acid-catalyzed hydrolysis to obtain α-L-rhamnosyl-1-hydrogen phosphite diester intermediate; use oxidative coupling method to react with the nitrogen end of bright-colored dipeptide benzyl ester to obtain phosphoramide precursor ; Finally, "one-pot method" hydrogenation and deacetylation to remove all the protective groups of the phosphoramide precursor, and purified by Sephadex gel chromatography to obtain high-purity phosphoramidone. The present invention designs and optimizes the protective groups of the three synthetic fragments of L-rhamnose, phosphitylation reagent and leucopeptide, simplifies the deprotection steps of the product precursor to the greatest extent, and utilizes novel hydrogen phosphorous acid The method of diester intermediate and oxidative coupling greatly improves the yield of the target product, and establishes a new method for the chemical synthesis of phosphoramidone.

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 ( Streptomycestanashiensis ) 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-likeproteinases, TLPs) have good thermal stability and protein cleavage activity, and are widely used in biochemistry, molecular biology, genetics, immunology, oncology, cell engineering, etc. Many frontier fields of biology and medicine. For example, thermolysin is used for protein sequence an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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