Trace Level Quantification of Derivatized Boronic Acids by LC/MS/MS

Abstract

Boron-containing compounds are often controlled as potentially mutagenic impurities based on ICH M7 guidance in drug substances. Herein, we describe a simple method to derivatize a subset of organoborons, non-nitrogencontaining aryl boronic acids, in order to quantify trace levels remaining in a drug substance using LC/MS/MS. Through this derivatization we are able to increase the sensitivity, demonstrate linearity, and spiked analyte recovery in matrix down to low parts per million (ppm) levels. The feasibility of this method is proven as three different examples are described, two in which one boronic acid may be present in a drug substance and one where two boronic acids may be present in the final product.

A Mild Method for Making MIDA Boronates

“…Methyliminodiacetic acid (MIDA) boronates are bench-stable building blocks with many applications. These include automated Lego-like small-molecule synthesis, manual syntheses of many different types of natural products, as well as drug candidates for cancer, , Parkinson’s disease, fibrosis, bacterial infections, and HIV, polymer science, preparation of complex boronic acids, ligands for characterization of approved pharmaceutical ingredients, liquid crystal technology, and numerous others However, access to many potentially impactful MIDA boronates is hampered by limitations in the methods that are typically used to prepare these building blocks.…”

A Convenient, Rapid, Conventional Heating Route to MIDA Boronates

“…Indeed, the samples that were subjected to our new were rather broad in scope, encompassing boronic acids based on an aryl 1, isox MIDA boronates occupy a central role in organic synthesis with many applications including, but not limited to, masked boronic acids in total synthesis [8][9][10]; catalysis [11][12][13][14][15][16][17], including iterative or telescopic couplings [17][18][19][20][21]; oxidation chemistry [22] or as C1 or C2 building blocks [23,24]. Although traditionally made by a Dean-Stark protocol, usually employing DMSO as solvent [25][26][27][28], many recent methods have shifted towards milder reaction conditions, more convenient work-up, purification and isolation techniques, notably to enable the synthesis of unstable esters such as 2-phenol [12] or 2-hetero-aryl MIDA analogues [29]. We wish now to disclose a conventional, sealed, heating reactor-based synthesis of MIDA boronates that offers a cheaper, effective alternative to our earlier disclosed microwave-mediated route [30].…”

Continuous Flow as Enabling Technology: Synthesis of Heteroaromatic Sulfinates as Bench Stable Cross-Coupling Partners

“…13 An additional aspect relates to preclinical safety and the high likelihood of boronic acid derivatives to trigger an in silico alert for mutagenicity, which can require the development of challenging and time-consuming analytical control and testing strategies. 14,15 In this context, the substitution of heteroaryl boronic acid derivatives by their corresponding sulfinate salts opens the opportunity to circumvent the above-mentioned concerns and allows access to a complementary cross-coupling strategy. Recently, Willis et al described the use of heteroaryl sulfinates (especially pyridyl) as alternative nucleophilic partners for palladium-catalyzed C(sp 2 )−C(sp 2 ) cross-couplings.…”

“…Although these measures can improve the stability of the coupling partner, they are in contrast to the green chemistry principals due to reduced atom efficiency as well as generation of extra organic waste and boron-containing aqueous waste streams . An additional aspect relates to preclinical safety and the high likelihood of boronic acid derivatives to trigger an in silico alert for mutagenicity, which can require the development of challenging and time-consuming analytical control and testing strategies. , …”

“…Various methodologies for the preparation of aryl (and some heteraryl) sulfinate salts have been described as outlined in Scheme . , Aryl and heteroaryl sulfinates are accessible via redox or other reactions of prefunctionalized organosulfur compounds ( A ). Sulfinative approaches ( B ) occur either via palladium-catalyzed sulfination of aryl halides ,− or by reaction of an organometallic species with electrophilic SO 2 or its surrogate DABSO. ,− Of note, aryl sulfinates are rarely described as isolated compounds and are typically used in situ for consecutive reactions …”