A Quantitative Assay of Sodium Triacetoxyborohydride

Article abstract of DOI:10.1021/acs.oprd.9b00215

Sodium triacetoxyborohydride (STAB) is a common reducing agent with potency that degrades over time and is not uniformly assigned. A simple assay based on an aldehyde reduction has been developed to determine the active borohydride content of this reagent. The HPLC assay yield of a salicylaldehyde reduction has been shown to accurately determine this potency and has been validated against the H₂ evolution method as well as yields obtained from a reductive amination. The use of these assay data to adjust the STAB charge as well to optimize a reductive amination has been demonstrated.

Full text of DOI:10.1021/acs.oprd.9b00215

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A Quantitative Assay of Sodium Triacetoxyborohydride
Michael Jason Zacuto, Joseph Perona, and Robert Dunn
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00215 • Publication Date (Web): 07 Aug 2019
Downloaded from pubs.acs.org on August 7, 2019
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Organic Process Research & Development
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A Quantitative Assay of Sodium
Triacetoxyborohydride
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Michael J. Zacuto,* Joseph Perona, and Robert Dunn
Drug Substance Development, Celgene Corporation, 556 Morris Avenue, Summit, NJ 07901,
USA
mzacuto@celgene.com
Br
Br
NaBH(OAc)3
MeCN 22 oC
OH
CHO
OH
OH
HPLCAssay yield of alcohol correlated to:
1) independent assay (H2 evolution)
2) reductive amination yield
Abstract: Sodium triacetoxyborohydride (STAB) is a common reducing agent with potency that
degrades over time and is not uniformly assigned. A simple assay has been developed to determine
the active borohydride content of this reagent, based on an aldehyde reduction. The HPLC assay
yield of a salicylaldehyde reduction has been shown to accurately determine this potency, and has
been validated against the H2 evolution method, as well as yields obtained from a reductive
amination. Use of this assay data to adjust a STAB charge, as well to optimize a reductive
amination, has been demonstrated.
Keywords: sodium triacetoxyborohydride, potency assay, hydrogen evolution, reductive
amination
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. INTRODUCTION
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Sodium triacetoxyborohydride (STAB)1 is a widely employed reducing agent for reductive
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amination reactions.2 As a water- and air-sensitive reagent, the potency of a particular lot of
reagent, once opened, is expected to gradually decrease over time. Accordingly, we have found
the need to add more reagent to a given reaction at a fixed scale as the supply ages. A convenient
assay for this reagent would alleviate the uncertainty associated with this charge.
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An accurate potency measurement could have several advantages with respect to the large-
scale use of STAB. Knowing the actual strength of the solid can help users predict an accurate
minimal charge required for full conversion, as opposed to the “excess” typically recommended.2
This has implications for the cost associated with the commercial reagent, as well as the thermal
and H2-evolution hazards that accompany quench of the excess charge. Furthermore, added control
could be leveraged in cases where excess reagent is detrimental to batch performance due to either
competing reactivity3 or to product stability concerns in the presence of excess borate/borohydride
salts.4 Incorporation of a simple assay into acceptance criteria of a large-scale supply prior to use
would also help ensure reagent quality under GMP conditions.
During a recent API synthesis campaign, we discovered that a 50 kg batch of STAB that
was purchased based on a listed specification of 97% was in fact significantly less potent, at
~67%.5 A subsequent survey of numerous suppliers revealed specifications of ≥80% or 95-97%
purity based on “titration.” Further investigation revealed a significant lack of information in many
cases as to the type of titration used or the associated procedure, and in those cases where
information was available, the titration method varied from vendor to vendor and few, if any,
further details were available.6
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STAB is prepared by the addition of solid NaBH4 to a solution of AcOH in a solvent
(typically DMAc or toluene), followed by filtration of the resulting solids.7 The purity of the
isolated solid depends on the efficiency of the reaction itself, as well as the washing and drying
protocols. Our experiences suggest that purity assays based on titration do not necessarily correlate
to the performance of the reagent during reductive amination reactions. For example, acid/base
titration results reported “as boric acid” or “as acetic acid” do not specifically indicate the wt% of
the active borohydride species. Additionally, the reactivity of the solid towards air and moisture
necessitates periodic re-assignment of the potency (wt%) with use and/or sampling.8
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There are no known reports in the literature with regards to an analytical assay for STAB.
By contrast, significant work has been reported regarding assay determination of sodium
borohyride (NaBH4),9 and a wide variety of methods have been developed. These include, but are
not limited to, H2 evolution, quantitative FTIR, aqueous acid/base titrations, and the aqueous iodate
method. We anticipated that adaptation of these assays would be complicated by the significant
difference in reactivity between NaBH4 and STAB and by the instability of the reagent to aqueous
conditions.10 Furthermore, our attempts to develop direct analytical techniques- such as elemental
analysis and quantitative 1H NMR- were unsuccessful.11
We therefore sought to develop an indirect assay. Specifically, we envisioned an aldehyde
reduction as a measure of STAB potency (Scheme 1) whereby an alcohol is formed12 and the yield
of this reaction reflects the amount of active STAB that was present in the added sample. In
principle, a reductive amination use test would also be useful, but we envisioned an independent
assay that isolates the influence of a particular batch of STAB on a reductive amination.13 Our
requirements were that the reaction was high yielding and used inexpensive, readily available
materials with no special equipment beyond an HPLC. We report herein the successful realization
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