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Syntheses of C‐13 and C‐14‐labeled versions of the investigational proteasome inhibitor MLN9708
Author(s) -
Plesescu Mihaela,
Elliott Eric L.,
Li Yuexian,
Prakash Shimoga R.
Publication year - 2013
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3079
Subject(s) - chemistry , proteasome inhibitor , adme , ixazomib , stereochemistry , proteasome , carfilzomib , biochemistry , in vitro
MLN9708 (ixazomib citrate) is an investigational, orally bioavailable proteasome inhibitor that is under development by Millennium in clinical studies in both hematologic and nonhematologic malignancies. The stable isotope‐labeled MLN9708 was required for bio‐analytical studies. [ 13 C 9 ]‐MLN9708 (11) was synthesized in seven steps from the uniformly labeled [ 13 C 6 ]‐1,4‐dichlorobenzene (3) and [1‐ 13 C]‐acetyl chloride. Because of the presence of two chlorine atoms and a boron atom, compound 6 was further reacted with [ 13 C 2 ]‐glycine to provide an internal standard that is well separated from the parent compound during mass spectrometric analysis. The radiolabeled version was prepared to support metabolite profiling and whole body autoradiography studies in experimental animals. [ 14 C]‐MLN9708 (19) was synthesized in six steps from commercially available [ 14 C]‐barium carbonate. The key intermediate, [carboxyl‐ 14 C]‐2,5‐dichlorobenzoic acid (14), was prepared by selective lithiation of 1‐bromo‐2,5‐dichlorobenzene (12) followed by carbonation with [ 14 C]‐barium carbonate. In preparation for a one‐time human absorption, distribution, metabolism and excretion (ADME) study, the stability of [ 14 C]‐MLN9708 and its precursors were also evaluated. Copyright © 2013 John Wiley & Sons, Ltd.