Chemoselective Removal of Dimeric 1,3-Diol Impurities Generated from Methyl Grignard Addition onto Esters

Abstract

In two separate cases, we have found that 1,3-diol dimeric impurities were common byproducts generated from the methyl Grignard addition onto esters to form the corresponding tertiary alcohols. These impurities proved difficult to purge by recrystallization as they tended to cocrystallize with the desired product. To avoid the necessity of chromatography, we developed a practical procedure for the chemoselective removal of these 1,3-diol impurities from crude tertiary alcohol by simply performing the recrystallization in the presence of phenylboronic acid. This straightforward method proved equally successful for two cases studied, and the procedure was later demonstrated on a multikilogram scale.

A one-pot diastereoselective synthesis of 1,3-diols and 1,3,5-triols via cascade reactions of arylalkynyl Grignard reagents with enol esters

“…Initially, intermediate A was formed through the 1,2-addition between ArC=CMgBr and 1, which would then produce B and enolate magnesium bromide C. Then D was formed through the rearrangement of B and C through an intermolecular aldol reaction as a reverse O-acylation. [42][43][44] Finally, the arylalkynyl Grignard reagent reacts with D to form the anti/syn-1,3-diol 4. 30 Simultaneously, the enolate magnesium bromide can react with D to form intermediate F through C-acylation which then further reacts with the arylalkynyl Grignard reagent to form G and finally produces 1,3,5-riols 5 with different configurations.…”

Rational Solvent Selection for Pharmaceutical Impurity Purge

“…The most extensive experimental study was reported for elimination of 1,3-diol dimeric impurities generated during methyl Grignard addition to esters. 6 A crude tertiary alcohol (Table 1) contained ∼3% of dimers. Recrystallization from 9 solvent systems resulted in variation of the 1,3-diol impurity content in the tertiary alcohol within 1.94%.…”

“…Two published pharmaceutically relevant experimental observations of the solvent effect on impurity purge via recrystallization were used in this study for testing of the proposed purge factors. , The API/impurity systems and results of impurity purging experiments reported in those studies are summarized in Table .…”

“…For example, in order to avoid the necessity of chromatography, a chemoselective removal of 1,3-diol impurities from crude tertiary alcohol by performing the recrystallization in the presence of phenylboronic acid was reported. 6 The applicability of complexing agent strategy was demonstrated for greater than 90% purification of the active pharmaceutical ingredient (API) fenofibrate from its major impurity fenofibric acid. 7 In addition, a strategy for combination of impurity complexation with nanofiltration membrane during continuous crystallization was recently reported.…”

“…Both of these approaches can be used to sterically prevent impurity incorporation into the host lattice. For example, in order to avoid the necessity of chromatography, a chemoselective removal of 1,3-diol impurities from crude tertiary alcohol by performing the recrystallization in the presence of phenylboronic acid was reported . The applicability of complexing agent strategy was demonstrated for greater than 90% purification of the active pharmaceutical ingredient (API) fenofibrate from its major impurity fenofibric acid .…”