Boronic acid derivatives and synthesis thereof
Inventors
Hecker, Scott J. • Boyer, Serge Henri • Dielemans, Hubertus J. A. • Gonzalez de Castro, Angela • De Vries, Andreas H. M. • Lefort, Laurent
Assignees
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Publication Number
US-11286270-B2
Publication Date
2022-03-29
Expiration Date
Abstract
Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs).
Core Innovation
The invention relates to methods of making a compound of formula (I) or pharmaceutically acceptable salt thereof by using protected carboxylic acid intermediates and sequential conversion through defined formula intermediates. The methods comprise reacting a compound of formula (A-I) with a borylating agent to form an organoboron intermediate, converting the organoboron intermediate to a compound of Formula (A-III), and hydrolyzing the compound of Formula (A-III) to form the compound of Formula (I), wherein R1 is a carboxylic acid protecting group.
A further aspect converts a compound of formula (A-II) to a compound of Formula (A-III) and then hydrolyzes the compound of Formula (A-III) to form the compound of Formula (I), with R1 as a carboxylic acid protecting group and Ra as OH or optionally substituted —O—C1-6 alkyl. The document also describes an optional chiral complex (A-II′) formed using one or more chiral auxiliaries, followed by reaction with a cyclopropylating agent to generate an optionally substituted 4-7 membered heterocyclyl ring.
Another aspect prepares a compound of Formula (A-I) via an alkylating route, by reacting a compound of formula (A-V) with an alkylating agent to form a compound of formula (A-VI), converting the compound of formula (A-VI) to the compound of formula (A-I), and defining R1 as a carboxylic acid protecting group. Related preparation includes preparing a compound of Formula (A-I′) by reacting (A-V) with an alkylating agent to form (A-VI′), converting (A-VI′) to (A-I), and hydrolyzing (A-I) to form (A-I′), while constraining substituent classes for R3 and ring formation when R3 groups combine.
Claims Coverage
The independent claims center on preparing compounds of Formula (I) and related intermediates through borylation, hydrolysis, cyclopropylating-agent conversion, and alkylation-based routes. In total, the inventive features include organoboron intermediate conversion and hydrolysis to Formula (I), conversion of Formula (A-II) to Formula (A-III) with hydrolysis, chiral-complex cyclopropylation, alkylation from (A-V) to (A-VI) or (A-VI′), base hydrolysis to (A-IV), and compound definitions with R1 and R3/ring constraints.
Organoboron intermediate conversion and hydrolysis to formula (I)
Reacting a compound of formula (A-I) with a borylating agent to form an organoboron intermediate, converting the organoboron intermediate to a compound of Formula (A-III), and hydrolyzing the compound of Formula (A-III) to form the compound of Formula (I), wherein R1 is a carboxylic acid protecting group.
Conversion of formula (A-II) to formula (A-III) and hydrolysis to formula (I) with Ra defined
Converting a compound of formula (A-II) to a compound of Formula (A-III) and hydrolyzing the compound of Formula (A-III) to form the compound of Formula (I), wherein R1 is a carboxylic acid protecting group and Ra is OH or optionally substituted —O—C1-6 alkyl.
Chiral complex cyclopropylation followed by hydrolysis to formula (I)
Reacting a chiral complex having the structure of formula (A-II′) with a cyclopropylating agent to form a compound of formula (III) and hydrolyzing the compound of Formula (A-III) to form the compound of Formula (I), wherein R1 is a carboxylic acid protecting group and Rc and Rd with any intervening atoms form an optionally substituted 4-7 membered heterocyclyl ring.
Alkylating-agent conversion via A-V to A-VI and to A-I
Preparing a compound of Formula (A-I) by reacting a compound of formula (A-V) with an alkylating agent to form a compound of formula (A-VI), converting the compound of formula (A-VI) to the compound of formula (A-I), wherein R1 is a carboxylic acid protecting group and each R3 is independently an optionally-substituted C1-6 alkyl, or two R3 together are optionally substituted C2-3 alkylene and form an optionally substituted 5-6 membered heterocyclyl ring with intervening atoms.
Alkylating A-V to A-VI′, converting to A-I, and hydrolyzing to form A-I′
Preparing a compound of Formula (A-I′) by reacting a compound of formula (A-V) with an alkylating agent to form a compound of formula (A-VI′), converting the compound of formula (A-VI′) to a compound of formula (A-I), and hydrolyzing the compound of Formula (A-I) to form the compound of Formula (A-I′), wherein R1 is a carboxylic acid protecting group.
Hydrolyzing with a base to form compound (A-IV)
A method of preparing a compound of formula (A-IV) comprising hydrolyzing with a base to form the compound of formula (A-IV).
Compound structure defined by R1 and R3/ring constraints
A compound having a structure wherein R1 is a carboxylic acid protecting group and each R3 is independently an optionally-substituted C1-6 alkyl, or two R3 together are optionally substituted C2-3 alkylene and form an optionally substituted 5- or 6-membered heterocyclyl ring with intervening atoms.
The claims collectively cover protected carboxylic acid intermediates used to access Formula (I) through borylating-agent organoboron intermediates and through A-II/A-III conversion with hydrolysis, including a chiral-complex cyclopropylating route. Additional coverage includes alkylating-agent sequences from A-V to A-VI or A-VI′, hydrolysis to A-I′, a base hydrolysis step to A-IV, and structural definitions using R1 and R3/ring-size constraints.
Stated Advantages
Pseudoephedrine gives the highest enantiomeric excess toward the desired enantiomer.
Documented Applications
Enantioselective cyclopropanation screening of chiral amino-alcohol auxiliaries using an oxaborin substrate, with conversion, yield, and enantiomeric excess measurements reported.
Use of stereochemical inversion behavior in ephedrine/pseudoephedrine·Ph2BH adducts to support enantioselective outcomes in cyclopropanation.
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