Synthesis of (S)-3-amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and SNAr reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials

Article abstract of DOI:10.1016/j.tetlet.2017.05.001

Two new synthetic routes were developed to prepare the RIP1 kinase inhibitor clinical candidate GSK2982772 involving a key (S)-3-amino-benzo[b][1,4]oxazepin-4-one intermediate prepared via Mitsunobu and S_NAr cyclization reactions. Both routes are practical and cost effective compared to the initial medicinal chemistry route and are also applicable to kilogram scale-up to support on-going clinical studies.

Full text of DOI:10.1016/j.tetlet.2017.05.001

Accepted Manuscript
Synthesis of (S)-3-Amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and
S Ar Reaction for a First-in-Class RIP1 Kinase Inhibitor GSK2982772 in Clin-
N
ical Trials
Jae Uk Jeong, Philip A. Harris, James Kang, Lara Leister, Yunfeng Lan, Joseph
Romano, Xiaoyang Dong, Robert W. Marquis
PII:
S0040-4039(17)30564-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.001
TETL 48894
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 April 2017
28 April 2017
1 May 2017
Please cite this article as: Jeong, J.U., Harris, P.A., Kang, J., Leister, L., Lan, Y., Romano, J., Dong, X., Marquis,
R.W., Synthesis of (S)-3-Amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and S Ar Reaction for a First-in-Class
N
RIP1 Kinase Inhibitor GSK2982772 in Clinical Trials, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.05.001
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Synthesis of (S)-3-Amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and S Ar
N
Reaction for a First-in-Class RIP1 Kinase Inhibitor GSK2982772 in Clinical Trials
Jae Uk Jeong*, Philip A. Harris, James Kang, Lara Leister, Yunfeng Lan, Joseph Romano, Xiaoyang Dong,
Robert W. Marquis
Pattern Recognition Receptor DPU, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Two new synthetic routes were developed to prepare the RIP1 kinase inhibitor clinical candidate
GSK2982772 involving a key (S)-3-amino-benzo[b][1,4]oxazepin-4-one intermediate prepared
Received in revised form
Accepted
N
via Mitsunobu and S Ar cyclization reactions. Both routes are practical and cost effective
compared to the initial medicinal chemistry route and are also applicable to kilogram scale-up to
support on-going clinical studies.
Available online
2
017 Elsevier Ltd. All rights reserved.
Keywords:
RIP1 kinase inhibitor
Benzo[b][1,4]oxazepin-4-one
Mitsunobu
N
S Ar cyclization
9
Introduction
psoriasis, ulcerative colitis and rheumatoid arthritis.
GSK2982772 possesses high in vitro potency and excellent
kinase selectivity, which combined with has highly favorable
physicochemical and pharmacokinetic properties makes this a
highly attractive development candidate.
Receptor interacting protein 1 (RIP1) kinase has recently
emerged as a promising therapeutic target for the treatment of
1
-
multiple inflammatory diseases in TNF-mediated inflammation.
4
During our drug discovery efforts, (S)-3-amino-
benzo[b][1,4]oxazepin-4-one (1) (Figure 1) was identified as an
important pharmacophore as part of a RIP1 kinase inhibitor
NHBOC
5
series. This benzoxazepinone template 1 has also been employed
6
to treat other biological targets like β-secretase, angiotensin
F
NHBOC
CO
O
NaH
2
CO H
+
HO
2
H
7
converting enzyme (ACE) and inhibitor of apoptosis proteins
NO2
DMF, rt
77%
NO2
8
(
IAPs).
HATU
DIPEA
NHBOC
CO
H
2
, Pd/C
O
O
O
N
N
2
H
NHBOC
NH
MeOH, rt
O
N
O
N
DMSO, rt
65-80%
N
H
9
5-100%
NH
2
O
NH2
NH
O
O
NaH
MeI
O
O
1
GSK2982772
4N HCl
NH
2
NHBOC
IC50 = 1.0 nM in ADP-Glo enzyme assay
IC50 = 6.3 nM in U937 cellular assay
Oral AUC: rat 2.3, monkey 2.9 µg.h/mL
Oral bioavailability: rat 110, monkey 86 %
N
DMF, rt
N
2 2
CH Cl , rt
O
O
1
O
N
O
N
N
Figure 1. Structures of benzoxazepinone 1 and GSK2982772
NH
NH
O
HO
N
NH
Lead optimization of this series led to identification of
GSK2982772 (Figure 1), a first-in-class RIP1 kinase inhibitor
currently undergoing phase 2 clinical trials for the treatment of
HATU, DIPEA
DMSO, rt
N
O
GSK2982772A
50-60% for 3 steps
_
__________________
Scheme 1. The initial route to synthesize GSK2982772
∗ Corresponding author.
E-mail address: jae.u.jeong@gsk.com (J. U. Jeong)

2
Tetrahedron
The initial route for the synthesis of GSK2982772 required 6
steps (not including the preparation of triazole carboxylic acid),
which was described previously starting from 1-fluoro-2-
nitrobenzene and Boc-L-serine as shown in Scheme 1. This
chemistry could be successfully scaled-up up to the kilogram
scale, but we decided to fully evaluate different synthetic routes
to the key intermediate 1. Any viable alternative synthesis had to
be as efficient and cost effective compared to the initial synthesis
Employing either Boc or Cbz protected serine the coupling
step was good (54-60% yield), but the yield for the subsequent
Mitsunobu cyclization was poor (18-43% yield). To optimize the
cyclization we switched to the trityl protecting group, which
increased the steric bulk to promote cyclization due to the angle
5
,9
1
2
compression similar to the Thorpe-Ingold effect as well as
reduced the acidity of the NH proton to reduce potential side
reactions. This resulted in substantially increasing the yield of the
Mitsunobu cyclization step (3c to 4c) to 89%. However, the
major disadvantage using the trityl protecting group was that the
initial coupling step with trityl-L-serine became low yielding (9-
(
6 steps to GSK2982772 and good overall yields).
Herein, we report two new efficient synthetic routes using
different and readily available starting materials, with no
overlapping steps with the initial synthesis. Our new approaches
2
6%).
N
utilizing the Mitsunobu reaction and the S Ar reaction for
After extensive optimization, the preferred Mitsunobu route
intramolecular ether formation to prepare the 7-membered ring
looked promising as illustrated in Figure 2. Both routes used
different starting materials compared to the initial synthesis.
Neither route required the reduction of aryl nitro group which
was achieved in the initial synthesis (Scheme 1) using palladium
on carbon, but provided significant undesired color
contamination.
started with readily available (S)-3-(tert-butoxy)-2-((tert-
butoxycarbonyl)amino)propanoic acid 5 as a fully protected
starting material to improve yield for the amide coupling reaction.
It was coupled with 2-(methylamino)phenol using T3P and i-
2
Pr NEt to provide the coupling product 6 in high yield (89%).
Both protecting groups of 6 were simultaneously removed using
acidic conditions (4M HCl in dioxane) and the resulting free
amine 7 was protected with the optimal trityl protecting group.
Without any further purification, the trityl protected amine 3c
was cyclized to the desired product 4c via Mitsunobu reaction
3
using PPh and DEAD with good isolated yield (69% for 3 steps
from intermediate 6). The structure was also confirmed by a
small molecule x-ray structure as shown in Scheme 3. Although
this optimized route requires two additional steps to manipulate
the proper protecting groups, the overall yield is much better than
initial attempts using the Mitsunobu cyclization as shown in
Scheme 2 and the number of steps is comparable with the initial
route we were aiming to replace.
Figure 2. 7-Membered ring formation for benzoxazepinone
Results and Discussion
1
0
The key Mitsunobu cyclization using the standard conditions
was evaluated as shown in Scheme 2. Various protected L-
serines 2 were coupled with 2-(methylamino)phenol using the
commercially available and efficient coupling reagent for the
epimerization-prone substrates, T3P (n-propanephosphonic acid
1
1
anhydride) and i-Pr
2
NEt, followed by Mitsunobu cyclization
using PPh and DEAD to yield the cyclized products 4a-c.
3
Scheme 3. New synthetic route via Mitsunobu reaction
A second alternative approach we studied to prepare 1
involved a nucleophilic aromatic substitution (S
as shown in Scheme 4. The precursor 8 for the S
N
Ar) cyclization
Ar reaction was
N
initially prepared from the fully protected serine 5 and 2-fluoro-
N-methylaniline in one step using T3P or i-butyl chloroformate,
but the reaction was sluggish in general and provided moderate
yields (35-61%). Instead, the precursor 8 was prepared in 2 steps
Scheme 2. Initial attempts via Mitsunobu reaction

with better yield from the coupling reaction (88%) using 2-
fluoroaniline with T3P and i-Pr NEt, followed by N-methylation
94%) of 9 using methyl iodide. Although this added an
In conclusion, two new synthetic routes to prepare the amino
benzoxazepinone core 1 were successfully developed. Both
routes are viable alternatives to the initial route, have similar
cost-of-good analysis and are applicable for the scale up of
2
(
additional methylation step, these conditions were practical and
worked well on a large scale. After removal of both protecting
groups with acidic conditions (4M HCl in dioxane), the resulting
free amine 10 was protected with the optimal trityl protecting
group similar to the previous reactions shown in Scheme 3. The
trityl protected amine 11 was successfully cyclized to the
N
GSK2982772. The S Ar cyclization route was successfully
applied to prepare >5 kilogram batches of API. Further details for
the application of both routes will be reported in due course.
2 3
cyclized product 4c in high yield (86%) using Cs CO in DMF at
o
0 C.
Acknowledgments
5
The authors thank Minghui Wang and Grazyna Graczyk-
Millbrandt for their assistance with full characterization of key
compounds by NMRs.
A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/xxxxx
References
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N
Scheme 4. New synthetic route via S Ar cyclization
1
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.
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Finally, the key amino benzoxazepinone, (S)-3-amino-
benzo[b][1,4]oxazepin-4-one (1), was obtained from 4c after
deprotection using an acidic condition (4M HCl in dioxane) as
shown in Scheme 5, which was identical to the compound 1
using the initial route summarized in Scheme 1. This key amino
benzoxazepinone 1 was coupled with triazole carboxylic acid
using coupling agents such as HATU and T3P to complete the
9. Harris, P. A.; Berger, S. B.; Jeong, J. U.; Nagilla, R.;
Bandyopadhyay, D.; Campobasso, N.; Capriotti, C. A.; Cox, J. A.;
Dare, L.; Dong, X.; Eidam, P. M.; Finger, J. N.; Hoffman, S. J.;
Kang, J.; Kasparcova, V.; King, B. W.; Lehr, R.; Lan, Y.; Leister, L.
K.; Lich, J. D.; MacDonald, T. T.; Miller, N. A.; Ouellette, M. T.;
Pao, C. S.; Rahman, A.; Reilly, M. A.; Rendina, A. R.; Rivera, E. J.;
Schaeffer, M. C.; Sehon, C. A.; Singhaus, R. R.; Sun, H. H.; Swift,
B. A.; Totoritis, R. D.; Vossenkämper, A.; Ward, P.; Wisnoski, D.
D.; Zhang, D.; Marquis, R. W.; Gough, P. J.; Bertin, J. J. Med. Chem.
9
,13
synthesis of GSK2982772.
2
017, 60, 1247-1261.
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1
7
Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551-2651.
1. Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett. 2011,
13, 5048-5051.
2. Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735-1766.
1
1
Scheme 5. Final step for the benzoxazepinone core 1

4
Tetrahedron
1
3. The chiral purity of GSK2982772 was determined with the
following method: Chiral HPLC analysis using a Lux Cell 4
analytical column (150 mm × 4.6 mm), eluting with 10:90
3
MeOH:CH CN plus 0.1% isopropylamine as the mobile phase at
flow rate 1 mL/min, provided good separation of a racemic
standard. The desired S enantiomer GSK2982772 eluted at 3.99
min. The separately prepared R enantiomer (not shown) eluted at
7
.16 min. This indicated that the chiral purity of GSK2982772
prepared from the key intermediate 1 via the Mitsunobu reaction
and the S Ar reaction was >99.9% ee, with none of the R
enantiomer detected.
N

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Synthesis of (S)-3-Amino-
benzo[b][1,4]oxazepin-4-one via Mitsunobu
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N
and S Ar Reaction for a First-in-Class RIP1
Kinase Inhibitor GSK2982772 in Clinical
Trials
Jae Uk Jeong*, Philip A. Harris, James Kang, Lara Leister, Yunfeng Lan, Joseph Romano, Xiaoyang
Dong, Robert W. Marquis
Two new synthetic routes were developed to prepare the RIP1 inhibitor clinical candidate GSK2982772 involving a key
(
N
S)-3-amino-benzo[b][1,4]oxazepin-4-one intermediate prepared via Mitsunobu and S Ar cyclization reactions. Both
routes are practical and cost effective compared to the initial medicinal chemistry route and are also applicable to kilogram
scale-up to support on-going clinical studies.

6
Tetrahedron
Highlights
•
•
•
Two new synthetic routes to 3-amino-
benxoxazepin-4-one were developed.
Successful optimization for Mitsunobu and S
cyclization reactions.
N
Ar
Efficient and practical synthesis applicaple to
kilogram scale-up.