One-pot method for synthesizing chiral amino boronate intermediate

A technology for amino borate and intermediates, which is applied in the field of one-pot synthesis of chiral amino borate intermediates, which can solve problems such as difficult long-term storage, increased costs, and capacity limitations, and achieve the effect of simple operation and increased costs

Inactive Publication Date: 2013-07-17
CHENGDU AIQUN TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthesis method has serious disadvantages: four-step chemical transformation is required, the process steps are cumbersome, some process conditions are relatively harsh, and two-step reactions need to be carried out at ultra-low temperatures (minus 50 to minus 60 degrees Celsius), so a large number of industrial When producing this key intermediate for the synthesis of bortezomib, the production capacity will be greatly limited
[0017] (2) Big potential safety hazard
(For example, the method reported in patent CN101812026 requires hydrogenation reaction conditions, which requires extremely high equipment safety performance);
[0018] (3) The catalyst used is not easy to prepare, and its storage and use conditions are harsh
(For example, in patents CN101812026, CN101781326 and documents such as J.Am.Chem.Soc.2008, 130, 6910-6911, it is necessary to prepare imine compounds in advance—(R)-2-methyl-N-(3-methyl Butylene) propane-2-sulfinamide, which increases the experimental operation process and increases the cost, and the imine compounds are unstable and not easy to store for a long time

Method used

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  • One-pot method for synthesizing chiral amino boronate intermediate
  • One-pot method for synthesizing chiral amino boronate intermediate
  • One-pot method for synthesizing chiral amino boronate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] Add 1.21g (10mmol) of (R)-tert-butylsulfinamide, 1.03g (12mmol) of isovaleraldehyde and 2.71g (12mmol) of neopentyl glycol diborate into a 100ml reaction bottle, then add 50ml of tert-butyl methyl ether and stir Disperse and mix well, add 2g of anhydrous magnesium sulfate and 329mg (1mmol) of copper trifluorosulfonate under the atmosphere of nitrogen protection. After the addition is complete, let the reaction mixture react at room temperature for 48 hours. TLC monitors the progress of the reaction. After the reaction is completed, , add 50ml ethyl acetate to disperse the reaction liquid, then add 1N NaHCO 3 3 liters of aqueous solution was washed once, the upper organic phase was washed three times with saturated brine, the aqueous phase was separated and discarded, the organic phase was stirred and dried with an appropriate amount of anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the compound R-N-(R-tert-bu...

Embodiment 2

[0042]

[0043] Add 1.21g (10mmol) of (S)-tert-butylsulfinamide, 1.03g (12mmol) of isovaleraldehyde and 2.71g (12mmol) of neopentyl glycol diborate into a 100ml reaction bottle, then add 50ml of dichloromethane and stir Disperse and mix well, add 2g of anhydrous sodium sulfate and 180mg (1mmol) of copper propionate under the atmosphere of nitrogen protection, after the addition is complete, let the reaction mixture react at 0°C for 48 hours, monitor the progress of the reaction by TLC, after the completion of the reaction , add 50ml ethyl acetate to disperse the reaction liquid, then add 1NNaHCO 3 3 liters of aqueous solution was washed once, the upper organic phase was washed three times with saturated brine, the aqueous phase was separated and discarded, the organic phase was stirred and dried with an appropriate amount of anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the compound S-N-(S-tert-butyl Sulfonyl)-1-amino-3-me...

Embodiment 3

[0045]

[0046] Add 1.21g (10mmol) of (R)-tert-butylsulfinamide, 1.03g (12mmol) of isovaleraldehyde and 3.04g of (2-methyl-2,4-pentanediol) diboronic acid into a 100ml reaction bottle ( 12mmol), then add 50ml tetrahydrofuran and stir to disperse and mix evenly. Under the atmosphere of nitrogen protection, add 2g of cesium carbonate and 100mg (1mmol) of cuprous chloride. After the addition is complete, let the reaction mixture react at room temperature for 48 hours. , after the reaction is complete, add 50ml of ethyl acetate to disperse the reaction solution, then add 1N NaHCO 3 3 liters of aqueous solution was washed once, the upper organic phase was washed three times with saturated brine, the aqueous phase was separated and discarded, the organic phase was stirred and dried with an appropriate amount of anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the compound R-N-(R-tert-butyl Sulfonyl)-1-amino-3-methylbutane-1-boronic...

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Abstract

The invention discloses a one-pot method for preparing a chiral amino boronate intermediate. According to the invention, three components of a chiral amine source, an aldehyde source and a boron source are subjected to a one-step reaction under the effect of a dehydration agent and a catalyst, such that a chiral alpha-amino boronate intermediate is obtained. With a simple de-protection treatment, a series of chiral alpha-amino boronate with various structures can be rapidly prepared. According to the chiral alpha-amino boronate preparation method disclosed by the invention, an unstable imine compound is not required to be prepared in advance; operation steps are simplified; production cost is low; operation is simple; and the method is suitable for industrialized productions.

Description

Technical field: [0001] The invention relates to a "one-pot method" method for synthesizing a chiral α-amino borate intermediate. Background technique: [0002] Boronic acid compounds are an extremely important class of organic compounds. Due to their unique structural characteristics, good biological activity and pharmacological effects, they are widely used in the synthesis of potential enzyme inhibitors and feedback-controlled drug transport polymers. And α-aminoboronic acid is more considered as the pharmacophore of serine protease inhibitors. This type of inhibitor can reversibly occupy the space where the enzyme and the substrate interact, so that the proteolytic enzyme cannot bind to the substrate polyprotein and hydrolyze the corresponding serine protease inhibitor. Peptide bonds, thus being made into inhibitors of various proteases including thrombin, endopeptidase and dipeptidyl peptidase (such as compound E). And serine protease can also regulate intracellular an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/04
Inventor 张明
Owner CHENGDU AIQUN TECH
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