Enabling Synthesis of ABBV-2222, A CFTR Corrector for the Treatment of Cystic Fibrosis

Article abstract of DOI:10.1021/acs.orglett.9b02099

An enabling preclinical synthetic route to cystic fibrosis candidate ABBV-2222 is described. Two stereoselective steps provide access to an aminochroman intermediate with excellent control, and a late-stage demethylation/difluoromethylation sequence provides efficient access to the target molecule.

Full text of DOI:10.1021/acs.orglett.9b02099

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enabling Synthesis of ABBV-2222, A CFTR Corrector for the
Treatment of Cystic Fibrosis
Stephen N. Greszler,* Bhadra Shelat, and Eric A. Voight
Research & Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
*
S Supporting Information
ABSTRACT: An enabling preclinical synthetic route to cystic fibrosis candidate ABBV-2222 is described. Two stereoselective
steps provide access to an aminochroman intermediate with excellent control, and a late-stage demethylation/
difluoromethylation sequence provides efficient access to the target molecule.
ystic fibrosis (CF) is a multiorgan disease that affects
more than 70,000 people worldwide. Caused by a
compound currently in clinical trials. Herein, we describe the
results of those efforts and the successful implementation of
this route in the delivery of >100 g of ABBV-2222 for
advanced preclinical characterization.
Our original synthetic target and lead compound was 1,
which bore a methoxy group at C7 in contrast to the
difluoromethoxy group of ABBV-2222 (Scheme 1). Retro-
C
deficiency or defect in the cystic fibrosis transmembrane
conductance regulator protein (CFTR), its effects are widely
observed among the lungs, sinuses, pancreas, and gastro-
1
intestinal tract. Hundreds of the nearly 2000 known
mutations to the CFTR protein have been attributed to
causing the onset of disease, and these defects are grouped into
several classes based on functional impact: trafficking,
Scheme 1. Retrosynthetic Analysis of 1 and ABBV-2222
1
production, function, and/or stability. In the subset of
patients with a homozygous F508del mutation, where
phenylalanine 508 is omitted, both a reduced quantity of
matured CFTR channels at the cell surface and gating
mutations (nonfunctional wild-type levels of CFTR ion
channels on the cell surface) are known to contribute to the
disease. Two classes of modulators are required for these
patients: potentiators to effect opening of the CFTR channels
at the cell surface and correctors to increase the number of
1c,2a
functional channels.
As part of a program devoted to the
development of improved treatments for CF, we were tasked
with identifying a viable synthetic route to enable rapid
delivery of large quantities of material to support preclinical
studies with lead ABBV-2222 (Figure 1), a potent corrector
synthetic analysis of this compound employed a late-stage
amide coupling of amine hydrochloride 2 with the
corresponding carboxylic acid fragment common to both
target molecules. Encouraged by preliminary results from
2
original analog syntheses employing the asymmetric Michael
3
addition (Stoltz−Hayashi) of 4-carbomethoxyphenyl boronic
acid to the corresponding chromenone 4, we chose to utilize
the existing asymmetric approach to set the first stereocenter.
This allowed us to focus our efforts on the stereoselective
introduction of the primary amine through diastereoselective
reductive amination.
Received: June 18, 2019
Figure 1. Structure of ABBV-2222.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02099
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Organic Letters
Letter
Our efforts commenced with the synthesis of chromenone 4,
a commercially available compound which could also be
conveniently prepared through condensation of 2-hydroxy,4-
methoxyacetophenone with DMF-DMA (Scheme 2). With
on its predicted human dose and requested its late-stage
substitution for compound 1 prior to candidate selection.
2a
With the close structural similarity of ABBV-2222 to
compound 1, we considered de novo synthesis of the
corresponding C-7 difluoromethoxy analog of 2. However,
because substantial external sourcing of the intermediate was
already underway and preliminary experience with the oxime
reduction revealed challenges with electron-deficient sub-
Scheme 2. Asymmetric Flavanone Synthesis via Stoltz−
Hayashi Addition
7
strates, we chose instead to attempt late-stage introduction
of the difluoromethoxy group from available intermediates
(
Scheme 4).
Scheme 4. Amide Coupling and Methyl Ether Deprotection
sufficient supply of the Michael acceptor in hand, we
investigated the addition of the boronic acid via asymmetric
3
Pd-catalyzed 1,4-addition reported previously by Stoltz. When
adapting the reaction to multigram scale, we generally
observed lower conversions and isolated yields than were
2
typically seen in smaller-scale reactions, but we were able to
8
accommodate these results because they occurred early in the
Amide formation from 2 through the acid chloride 6 cleanly
4
synthetic route. Workup consisted of filtration through a pad
afforded intermediate 7 in high yield (87%) after crystallization
from ethyl acetate/heptanes. We successfully scaled this
reaction to >200 g and subsequently evaluated demethylation
of the C7 aryl ether. Fortunately, we were able to cleanly
convert this material to the free phenol 8 after optimization of
conditions previously reported to be successful for aryl ethers.
We found that it was necessary to increase the amount of TBAI
and BCl in the reaction to 3.0 equiv in order to achieve high
conversion due to the additional Lewis basic functionalities
present. Although we observed a slight degree of concomitant
methyl ester deprotection (∼5%), these conditions were
successfully employed on 170 g scale. Crude material was
carried forward without additional purification after removal of
the tetrabutylammonium salts through precipitation with
5
of silica to remove the boronic acid and subsequent
crystallization to afford the desired product in 49% yield and
5
9
5% ee (Scheme 2).
Equipped with a reliable method for the synthesis of
9
flavanone 3, we proceeded to form the O-methyl oxime
through condensation with the corresponding hydroxylamine
in pyridine, which occurred uneventfully to give 5a in high
yield (Scheme 3). Similar O-methyl oximes previously allowed
3
Scheme 3. Oxime Formation and Diastereoselective
Reduction
5
MTBE and filtration.
The completion of the enabling synthesis of ABBV-2222
required a difluoromethylation of phenol 8 and a final
saponification (Scheme 5). We initially performed these
Scheme 5. Endgame Alkylation and Saponification
for diastereoselective synthesis of the corresponding primary
6
amines via hydrogenation catalyzed by Pt/C in acetic acid, yet
this particular intermediate was plagued by insolubility in
HOAc that resulted in only complex product mixtures and
poor conversion to the desired amine. Preparation of the O-
benzyl oxime 5b, however, occurred in similar yield and
resulted in a product fully soluble in the hydrogenation solvent.
We initially observed a 13:1 crude diastereomeric mixture but
conveniently upgraded both the diastereo- and enantiopurity
through formation of the hydrochloride salt in a mixture of
steps separately but ultimately developed a high-yielding one-
pot procedure that cleanly afforded the desired API. Alkylation
with diethyl (bromodifluoromethyl)phosphonate as a difluor-
5
MTBE and acetic acid. Product 2 was thus isolated in an
overall 79% yield from 5b with >50:1 dr and >98% ee.
Having established a viable route to key intermediate 2, we
demonstrated the synthesis of >30 g of this compound in-
house and initiated efforts to source several hundred grams
from external vendors while we evaluated downstream
chemistry. Concurrently, our medicinal chemistry colleagues
had identified ABBV-2222 as a superior lead molecule based
10
ocarbene source proceeded rapidly in 10 vol of MeCN at
−20 °C with 20 equiv of aqueous KOH (4 M) to give
intermediate 9. Addition of methanol homogenized the
reaction, and heating to 40 °C then effected complete
saponification of the methyl ester to give the crude product.
5
A final recrystallization of the API from MeOH/water
B
DOI: 10.1021/acs.orglett.9b02099
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Organic Letters
Letter
afforded a 76% yield of the desired product over three steps.
This successfully delivered >130 g of ABBV-2222 with high
purity (>99% potency) to support advanced preclinical studies.
In conclusion, we have reported the development of an
enabling asymmetric synthesis of the clinical candidate ABBV-
C.; Jia, Y.; Desino, K.; Gao, W.; Yong, H.; Tse, C.; Kym, P. J. Med.
Chem. 2018, 61, 1436−1449. (b) Altenbach, R. J.; Bogdan, A.;
Greszler, S. N.; Koenig, J. R.; Kym, P. R.; Liu, B.; Searle, X. B.; Voight,
E.; Wang, X.; Yeung, M. C. May 9, 2017, US Patent 9,642,831 B2.
(
3) Holder, J. C.; Marziale, A. N.; Gatti, M.; Mao, B.; Stoltz, B. M.
Chem. - Eur. J. 2013, 19, 74−77 and references therein .
4) Subsequent studies identified that increased oxygen levels
benefitted this reaction.
5) See the Supporting Information for details.
2222 that was utilized to provide >130 g of the desired API to
(
support preclinical studies. After successfully adapting an
asymmetric Stoltz−Hayashi addition of 4-carbomethoxyphenyl
boronic acid to 7-methoxy chromenone 4, we were able to
overcome challenges associated with the unexpected insol-
ubility of the key oxime intermediate and develop an efficient
diastereoselective route to the primary amine 2. A late-stage
substitution of ABBV-2222 for early lead compound 1 required
further development of a downstream methyl ether depro-
tection and one-pot difluoromethylation/saponification proto-
col that allowed us to salvage the existing quantities of 2 that
were already in hand. Using the route described here, we were
also able to perform the entire sequence without chromatog-
raphy to obtain high purity API through a total of 6 linear steps
and 26% overall yield from commercially available materials
(
(6) (a) Bognar, R.; Rakosi, M.; Fletcher, H.; Philbin, E. M.; Wheeler,
T. S. Tetrahedron 1963, 19, 391−394. (b) Bognar, R.; Clark-Lewis, J.
W.; Liptakne-Tokes, A.; Rakosi, M. Aust. J. Chem. 1970, 23, 2015−
2
(
025.
7) Electron-rich substrates performed well with this reduction, but
we generally encountered lower yields and complex mixtures of
reduction products with electron-deficient substrates; see ref 2 for
more details.
(
4). ABBV-2222 subsequently progressed into the develop-
ment phase, and its further progress through development will
be reported in due course.
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
8) For this work, the carboxylic acid was purchased from external
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02099.
vendors. For a concise synthetic route to cyclopropanecarboxylates
through Pd-catalyzed cross-coupling of Reformatsky reagents, see:
Greszler, S. N.; Halvorsen, G.; Voight, E. A. Org. Lett. 2017, 19,
2
(
490−2493.
9) Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.;
Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64,
719−9721.
(10) (a) Zafrani, Y.; Sod-Moriah, G.; Segall, Y. Tetrahedron 2009,
Experimental details and characterization data for all
new compounds (PDF)
9
AUTHOR INFORMATION
Corresponding Author
■
*
6
5, 5278−5283. (b) Lee, J. W.; Lee, K. N.; Ngai, M.-Y. Angew. Chem.,
Int. Ed. 2019, DOI: 10.1002/anie.201902243.
E-mail: stephen.greszler@abbvie.com.
ORCID
Stephen N. Greszler: 0000-0003-1993-2417
Eric A. Voight: 0000-0002-9542-5356
Notes
The authors declare the following competing financial
interest(s): All authors are employees of AbbVie. The design,
study conduct, and financial support for this research were
provided by AbbVie. AbbVie participated in the interpretation
of data, review, and approval of the publication.
ACKNOWLEDGMENTS
■
We thank the AbbVie Structural Chemistry group for
compound characterization support. We thank the Pressure
and Catalysis group for their support in hydrogenation reaction
development.
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DOI: 10.1021/acs.orglett.9b02099
Org. Lett. XXXX, XXX, XXX−XXX