Cu-and Ni-catalyzed decarboxylative borylation reactions

A boric acid, hybrid technology, applied in catalytic reaction, boron compound active ingredient, boron compound active ingredient, etc., to achieve the effect of high chemical selectivity and cheap reagents

Pending Publication Date: 2020-02-14
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(6) Despite their popularity, boronic acids are obtained almost entirely synthetically, unlike the ubiquitous and cheap carboxylic acid

Method used

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  • Cu-and Ni-catalyzed decarboxylative borylation reactions
  • Cu-and Ni-catalyzed decarboxylative borylation reactions
  • Cu-and Ni-catalyzed decarboxylative borylation reactions

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0142] [B 2 pin 2 Preparation of Me]Li complexes:

[0143] to B at 0°C under argon 2 pin 2 (1.1 eq.) in THF (B 2 pin 2 The concentration is 1.1M) to add MeLi (1.6M, in Et 2 O, 1.0 equiv). The reaction mixture was warmed to room temperature and stirred for 1 h to give a milky white suspension.

[0144] Nickel-catalyzed decarboxylation borylation:

[0145] Will be loaded with redox active ester (1.0 equivalent) and MgBr 2 ·OEt 2 (1.5 equivalents) of the flask was evacuated and backfilled three times with argon. Catalyst solution or suspension (containing 10 mol% NiCl 2 ·6H 2 O and 13 mol% ligand). When using a catalyst suspension / solution in DMF, add another portion of THF to the reaction vessel (twice the volume of the DMF suspension / solution required) followed by the catalyst mixture [this process can be quite exothermic. Cooling (with ice / water bath) may be necessary]. The resulting mixture was stirred vigorously until no visible solids were observed at the bot...

Embodiment

[0217] Boronic acid inhibitors of human neutrophil elastase prepared by the method of the invention

[0218] Disclosed compound (IC of human neutrophil elastase 50 )

[0219]

[0220] Synthetic pathway of boronic acid inhibitor of human neutrophil elastase

[0221]

[0222]

[0223] All three compounds (mCBK319, mCBK320 and mCBK323) were found to have a high tendency to trimerize in the boronic acid motif. The biological activity of these trimers may require further study. These novel elastase inhibitors have potential applications in the treatment of cancer, circulatory fibrosis and bronchiectasis.

[0224] These compounds showed higher potency (100-1000-fold increase compared to similar trifluoroquinoline lead compounds) than the lead compounds screened as elastase inhibitors. The unique physicochemical properties of the boronic acid motif can lead to favorable pharmacokinetic properties. The preparation methods disclosed herein are straightforward and easy to ...

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PUM

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Abstract

The invention is directed to methods of converting a carboxylic acid group in a compound, via a redox active ester, to a corresponding boronic ester by treatment with bis(pinacolato)diboron-alkyllithium complex in the presence of a ligand, a Ni(ll) salt or a copper salt, and an Mg(ll) salt, in the presence of an alkyllithium or a lithium hydroxide or alkoxide salt. The product pinacolato boronateester can be cleaved to provide a boronic acid. The invention is also directed to methods of preparing various compounds of medical value comprising boronic acid groups, and to novel boronic-acid containing compounds of medicinal value, including an atorvastatin boronic acid analog, a vancomycin aglycone boronic acid analog, and boronic acid containing elastase inhibitors mCBK319, mCBK320, mCBK323, and RPX-7009.

Description

[0001] Statement of Government Support [0002] This invention was made with government support under GM-118176 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0003] Boronic acid is essential to all aspects of chemical science. Although their popularity and widespread use can probably be attributed to the incredible utility of Suzuki couplers, (1) boric acids have so far found use in fields other than cross-coupling, such as materials science, (2) chemical sensors, (3) Polymer science, (2) and drug discovery find countless applications. (4-5) In medicine, FDA currently approves two alkylboronic acids for various oncological indications: ninlaro (1) and velcade (49). Medicinal chemists note that boronic acids are bioisomerizable because they can act as substitutes for carboxylic acids in some cases. (6) Despite their popularity, boronic acids are obtained almost entirely synthetically, unlike the ubi...

Claims

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Application Information

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IPC IPC(8): A61K31/69A61K33/22A61K38/06
CPCA61K38/08A61K31/69A61K33/22C07F5/025Y02P20/55B01J31/0212B01J2231/344B01J2531/16C07B47/00C07F5/027C07K7/64
Inventor 菲尔·巴兰李超王杰阿纳布·库马尔·查特吉马诺吉·库马尔于珊克里斯汀·安·约翰逊秦天商明
Owner THE SCRIPPS RES INST
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