Cu- and Ni-catalyzed decarboxylative borylation reactions

Patent metadata

Field	Value
Publication number	US-12415819-B2
Application number	US-202117449509-A
Country	US
Kind code	B2
Filing date	Sep 30, 2021
Priority date	Mar 21, 2017
Publication date	Sep 16, 2025
Grant date	Sep 16, 2025

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(II) salt or a copper salt, and an Mg(II) salt, in the presence of an alkyllithium or a lithium hydroxide or alkoxide salt. The product pinacolato boronate ester 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.

First claim

What is claimed is:

1. A method of preparing the Boc-protected boronic pinacolato ester compound of formula

comprising treating the compound

in an aprotic solvent, with bis (pinacolato) diboron (B 2 pin 2 ), in the presence of at least 20 mole % of a Mg(II) salt and of at least one molar equivalent a lithium compound comprising a (C1-C4) alkyllithium, a (C 1 -C 4 ) alkoxylithium, or lithium hydroxide, and at least 10 mole % of a Cu or Ni salt;
in the presence of a 1,3-dicarbonyl ligand forming with the Cu a compound of formula (M)

wherein R 1A and R 2A are each independently selected from the group consisting of (C1-C4) alkyl, trifluoromethyl, or phenyl;
or in the presence of a ligand of formula (L) comprising a bipyridyl of formula

wherein R 1 and R 2 are each independently selected from the group consisting of ed (C1-C4) alkyl or (C1-C4) alkoxy, n1 and n2 are each independently 0, 1, or 2, or of a 1,10-phenanthroline of formula

wherein R 3 and R 4 are each independently selected from the group consisting of (C1-C4) alkyl, (C 1 -C 4 ) alkoxy, and phenyl;
to provide the Boc-protected boronic pinacolato ester compound

2. A method of preparing the Boc-protected boronic pinacolato ester compound of formula

comprising treating the compound

in an aprotic solvent, with bis (pinacolato) diboron (B 2 pin 2 ), in the presence of at least 20 mole % of a Mg(II) salt and of at least one molar equivalent a lithium compound comprising a (C1-C4) alkyllithium, a (C1-C4) alkoxylithium, or lithium hydroxide, and at least 10 mole % of a Cu or Ni salt;
in the presence of a 1,3-dicarbonyl ligand forming with the Cu a compound of formula (M)

wherein R 1A and R 2A are each independently selected from the group consisting of (C1-C4) alkyl, trifluoromethyl, or phenyl;
or in the presence of a ligand of formula (L) comprising a bipyridyl of formula

wherein R 1 and R 2 are each independently selected from the group consisting of ed (C1-C4) alkyl or (C 1 -C 4 ) alkoxy, n1 and n2 are each independently 0, 1, or 2, or of a 1,10-phenanthroline of formula

wherein R 3 and R 4 are each independently selected from the group consisting of (C1-C4) alkyl, (C 1 -C 4 ) alkoxy, and phenyl;
to provide the Boc-protected boronic pinacolato ester compound

and further comprising cleaving the Boc group of the Boc-protected boronic pinacolato ester compound with trifluoroacetic acid, followed by condensation of the resulting free amino group with compound of formula

followed by cleavage of pinacolato boronate ester group with phenylboronic acid in aqueous HCl to provide the boronic acid mCBK320 elastase inhibitor compound of formula

3. A method of preparing the Boc-protected boronic pinacolato ester compound of formula

comprising treating the compound

in an aprotic solvent, with bis (pinacolato) diboron (B 2 pin 2 ), in the presence of at least 20 mole % of a Mg(II) salt and of at least one molar equivalent a lithium compound comprising a (C1-C4) alkyllithium, a (C 1 -C 4 ) alkoxylithium, or lithium hydroxide, and at least 10 mole % of a Cu or Ni salt;
in the presence of a 1,3-dicarbonyl ligand forming with the Cu a compound of formula (M)

wherein R 1A and R 2A are each independently selected from the group consisting of (C1-C4) alkyl, trifluoromethyl, or phenyl;
or in the presence of a ligand of formula (L) comprising a bipyridyl of formula -----

wherein R 1 and R 2 are each independently selected from the group consisting of (C1-C4) alkyl or (C 1 -C 4 ) alkoxy, n1 and n2 are each independently 0, 1, or 2, or of a 1,10-phenanthroline of formula

wherein R 3 and R 4 are each independently selected from the group consisting of (C1-C4) alkyl, (C 1 -C 4 ) alkoxy, and phenyl;
to provide the Boc-protected boronic pinacolato ester compound

and further comprising cleaving the Boc group and the boronate ester of the Boc-protected boronic pinacolato ester compound with trifluoroacetic acid, followed by condensation of the resulting free amino group with compound of formula

followed by cleavage of the t-Bu ester, to provide a boronic acid mCBK323 elastase inhibitor compound of formula

Assignees

• Scripps Research Inst

Inventors

• Baran Phil
• Li Chao
• Wang Jie
• Chatterjee Arnab K
• Kumar Manoj
• Yu Shan
• Johnson Kristen
• Qin Tian
• Shang Ming

Classifications

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title

• C07B47/00

  Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00 · CPC title

• B01J2531/16

  Copper · CPC title

• B01J2231/344

  Boronation, e.g. by adding R-B(OR)2 · CPC title

• B01J31/0212

  Alkoxylates · CPC title