Synthesis of PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of α-amino acids

Article abstract of DOI:10.1016/j.tet.2019.04.057

An efficient synthesis of PI3K inhibitor GDC-0077, featuring two consecutive Cu-catalyzed C–N coupling reactions, is reported. The described synthetic route involves a chemoselective Ullmann-type coupling of a chiral difluoromethyl-substituted oxazolidinone, a Cu-catalyzed N-arylation of L-alanine with high stereochemical integrity, and a high-yielding final amide bond formation step to produce GDC-0077 in >99.5 area % HPLC purity.

Full text of DOI:10.1016/j.tet.2019.04.057

Accepted Manuscript
Synthesis of PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of α-amino
acids
Chong Han, Sean M. Kelly, Theresa Cravillion, Scott Savage, Tina Nguyen, Francis
Gosselin
PII:
S0040-4020(19)30476-4
https://doi.org/10.1016/j.tet.2019.04.057
TET 30302
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 March 2019
Revised Date: 19 April 2019
Accepted Date: 23 April 2019
Please cite this article as: Han C, Kelly SM, Cravillion T, Savage S, Nguyen T, Gosselin F, Synthesis of
PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of α-amino acids, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.04.057.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of PI3K inhibitor GDC-0077 via a
stereocontrolled N-arylation of α-amino
acids
Leave this area blank for abstract info.
Chong Han,* Sean M. Kelly, Theresa Cravillion, Scott J. Savage, Tina Nguyen, and Francis Gosselin
Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco,
California 94080, United States

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of α-amino
acids
Chong Han,* Sean M. Kelly, Theresa Cravillion, Scott Savage, Tina Nguyen, and Francis Gosselin
Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient synthesis of PI3K inhibitor GDC-0077, featuring two consecutive Cu-catalyzed C–
N coupling reactions, is reported. The described synthetic route involves a chemoselective
Received in revised form
Accepted
Ullmann-type coupling of a chiral difluoromethyl-substituted oxazolidinone, a Cu-catalyzed N-
arylation of
L-alanine with high stereochemical integrity, and a high-yielding final amide bond
Available online
formation step to produce GDC-0077 in >99.5 area % HPLC purity.
©
2019 Elsevier Ltd. All rights reserved.
Keywords:
C–N coupling
N-arylation
Amino acids
Amidation
Stereocontrolled
1
. Introduction
2
. Results and discussion
Our retrosynthetic analysis of GDC-0077 (1) is depicted in
The phosphoinositide 3-kinase (PI3K) intracellular signaling
pathway and its downstream Akt and mTOR cascades have been1
shown to be activated by mutation in many forms of cancer.
Therefore, extensive research efforts have been focusing on
Scheme 1. Through the Cu-catalyzed N-arylation of -alanine 2
L
and a subsequent amide formation using ammonia, the final
target would be accessed from aryl bromide 3 which could be
prepared from the chemoselective Ullmann-type coupling of the
2
designing selective PI3K inhibitors as antitumor agents. GDC-
0
077 is a potent small molecule PI3Ka inhibitor with excellent
9
-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-
4
PI3K isoform selectivity that is currently in clinical development
for the treatment of HR+, HER2- breast cancer (Figure 1). In the
medicinal chemistry synthesis, the construction of the imidazole
ring and the chemoselective Ullmann-type coupling of
difluomethyl-substituted oxazolidinone suffered from moderate
d][1,4]oxazepine 4 and oxazolidinone 5. 4 could then be
prepared from the corresponding parent imidazole 6 through an
iodination sequence. Leveraging on our reported synthesis of
5
taselisib
containing
a
similar
tricyclic
5,6-
6
dihydroimidazobenzoxazepine moiety, imidazole 6 would be
3
yields and selectivity. Moreover, the Cu-catalyzed N-arylation of
derived from a condensation of previously reported cyclic
7
L-alanine was found to be exceedingly oxygen-sensitive and
amidine 7 with chloroacetaldehyde 8.
inconsistent, giving variable amounts (up to 30%) of an
undesired diastereomer across different batches. In order to
produce the GDC-0077 active pharmaceutical ingredient (API) to
supply the clinical trials and drug product development needs, we
were tasked to develop a robust synthesis amenable to multi-
kilogram scale manufacturing.
Figure 1. Structure of GDC-0077
Scheme 1. Retrosynthetic Analysis
1

2
Tetrahedron
The synthesis of 4 is depicted in Scheme 2
cyclic amidine 7 with chloroacetaldehyde 8 produced imidazole
. Selective iodination using NIS in DMF occurred cleanly at the
A
. C
C
o
C
nd
E
en
P
sa
T
tion
E
D
of MAcr
N
yst
Evaluation of other aqueous soluble ligands L2
fruitless due to excessive halogen scrambling or low conversion
(entries 6). We next turned to high-throughput
U
all
S
iz
C
ati
R
on
I
,
P
re
T
quiring purification by column chromatography.
–
L5 proved
6
undesired C-1 position at 25 ºC leading to the formation of
positional isomer 10a. Complete bis-iodination took place at
elevated temperature (60 ºC) affording 10b in 85% yield from 6,
which underwent iodo–magnesium exchange using EtMgBr and
subsequent protonation to provide the desired positional isomer 4
3
–
a
experimentation (HTE) approach in search of alternative reaction
conditions. A survey of a full combination of 8 ligands, 3 bases,
and 8 solvents in two 96-well plates revealed interesting
conditions consisting of L2 as the ligand, Cs CO as the base,
2
3
cleanly in 82% yield.
and 2-MeTHF as the solvent. In contrast to previously disclosed
results showing a high bromo–iodo scrambling rate using L2 as
4
,8
the ligand in either DMSO or MeCN, the reaction was found to
be very clean when 2-MeTHF was employed as the solvent and
Scheme 2. Synthesis of benzoxazepine 4
Cs CO was used as the base (entry 7–10) regardless of the
2
3
Table 1
ligands used. The fastest reaction rate could be obtained using L2
as the ligand (87% conversion by HPLC analysis) and further
increasing the stoichiometry of oxazolidinone 5 to 110 mol %
gave 98% conversion and 92% assay yield of the desired product
Optimization of chemoselective Cu-catalyzed coupling
reaction of 4 and 5
a
3
ascertained by quantitative HPLC analysis (entry 11).
Table 2
a
Optimization of Cu-catalyzed coupling reaction of 2 and 3
b
c
conv
%)
3/(3a+3b+3c)
entry
ligand
base
PO
solvent
(
(%)
1
2
3
4
5
6
7
8
9
L1
L1
L2
L3
L4
L5
L2
L2
L1
L3
L2
K
3
4
MeCN
MeCN
95
99
99
29
28
4
74:26
88:12
32:68
99:1
99:1
N/A
ancillary temp
time
(h)
b
b
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
entry 2 (equiv)
conv.
92
dr
ligand
(°C)
MeCN
1
2
3
4
5
6
7
2.0
3.0
3.0
3.0
3.0
3.0
3.0
-
-
100
100
90
2
2
1
1
1
2
5
94:6
98:2
95:5
94:6
95:5
95:5
87:13
MeCN
c
99
MeCN
L2
L4
L5
-
83
88
83
92
91
MeCN
90
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
87
99
56
50
98:2
15:85
97:3
99:1
96:4
90
K
Cs
Cs
Cs
3 4
PO
90
2
2
2
CO
CO
CO
3
3
3
-
80
1
0
d
e
a
1
1
98
2
Reaction conditions: 3 (1 mmol), 2 (1.2 equiv), Cu O (5 mol %),
3 4
ancillary ligand (20 mol %), K PO (3.0 equiv), solvent (0.5 M).
a
Reaction conditions: 4 (1.5 mmol), 5 (1.05 equiv), Cu(OAc)
2
(20 mol %),
b
ligand (30 mol %), base (2.0 equiv), solvent (0.5 M).
Determined by HPLC analysis of crude reaction mixture.
b
c
Determined by HPLC analysis of crude reaction mixture.
90% assay yield by quantitative HPLC analysis.
c
Normalized ratio with the total of 3, 3a, 3b, and 3c being 100.
We next focused on the coupling of L-alanine (2) with aryl
bromide 3 (Table 2). Pioneering work by Ma and co-workers
highlighted a dual role of α-amino acids as both the reactants and
the accelerating ligands in the Cu-catalyzed N-arylation reaction.
d
1
.1 equiv of 5 used.
e
9
9
2% assay yield by quantitative HPLC analysis.
A number of examples were subsequently reported from various
10
groups, including several in which additional ancillary ligands
11
were utilized. However, only a few studied the stereochemical
12
integrity of the N-aryl amino acid products.
Initial experiments revealed poor reproducibility with respect
to the level of stereochemical erosion (3 30%) leading to the
–
With benzoxazepine 4 in hand, we next evaluated the
chemoselective coupling with oxazolidinone 5. Employing the
optimal conditions (K PO , L1, MeCN) described in our
undesired diastereomer 11a′, which was attributed to the extreme
oxygen sensitivity for this coupling reaction. Evaluation of a
variety of copper salts including CuI, CuBr, Cu O, Cu(OAc) ,
3
4
4
2
2
published method paper gave 95% conversion but a mixture of
desired bromo product 3, halogen-scrambled iodo product 3a,
des-bromo product 3b, and bis-coupled product 3c (Table 1,
entry 1). The side products were minimized from a total of 26%
to 12% using Cs CO instead of K PO as the base (entry 2).
CuO, CuSO led us to focus on Cu O for further optimization as
4
2
it showed the best oxygen tolerability. Under a strictly inert
atmosphere, use of 3.0 equiv of -alanine (2) further mitigated
the risk of stereochemical erosion, providing a 98:2 dr of product
1a as opposed to a 94:6 dr when 2 equiv were used. (Table 2,
L
2
3
3
4
1
However, complete removal of the ligand L1 proved to be
challenging through downstream aqueous work-ups or
entry 2 vs entry 1). Additional ancillary ligands L2, L4, and L5
were examined but showed no improvement with respect to

3
either reaction rate or dr (entries 3
when the reaction was performed at temperatures below 100 ºC
entries 6 7 vs 2).
–
6). We also
A
ob
C
se
C
rve
E
d
P
lo
T
w
E
er
D
dr MApi
N
lot
U
p
S
la
C
nt
RI
PTshowed further improved robustness with an
an
d
average of approximately 1% of 11a′ over multiple development
(
–
runs on a decagram scale (Figure 3).
Figure 2. A time course experiment to probe the cause of
stereochemical erosion
Preliminary mechanistic investigation via an experiment
Figure 3. Reproducibility of Cu-catalyzed coupling of 2 and 3. Level
of the undesired diastereomer 11a′ determined by HPLC analysis of
crude reaction mixtures.
monitoring the level of 11a′ and
course of the reaction revealed the origin of stereochemical
erosion was presumably due to racemization of -alanine rather
D-alanine (2′) throughout the
L
than epimerization of product 11a. As shown in Figure 2 with
conversion of ArBr (3) to product (11a) shown in stacked
columns on the primary y-axis to the left and normalized
percentage of eroded stereoisomers (11a′ or 2′) in marked lines
reflecting dr or er on the second y-axis to the right, the level of
undesired diastereomer 11a′ remained at approximately the same
level once the starting material 3 was completely consumed after
Even with the extensive optimization of the reaction
conditions for the Cu-catalyzed coupling of 2 and 3, further
purging of the undesired diastereomer 11a′ would still be
required before conversion to the final product GDC-0077 (1) for
two reasons: no observed depletion of the resulting diastereomer
in the final stage and the exceedingly high purity requirement for
the API. Moreover, although the corresponding potassium salt of
11a was found to be very stable, attempt to isolate 11a in its free
acid form via crystallization unveiled its extreme oxygen
sensitivity with the major degradation product identified as the
aniline 12b, presumably through an oxidative decarboxylation
2
–
3 h, while the unreacted
racemizing to the corresponding
5:65 er after 20 h. The experimental results were in accord with
the proposed reaction pathway (Scheme 3) in which the -alanine
2′) derived from racemization of 2 reacted with aryl bromide 3
L
-alanine (2) in excess continued
D-alanine (2′), reaching to a
3
D
1
3
(
pathway analogous to Strecker degradation via intermediate
14
leading to the formation of the undesired diastereomer 11a′.
12a (Scheme 4). We resorted to an HTE approach in search for
a salt of 11a to improve its stability and further lower the level of
1
1a′. The corresponding ammonium salt 11b was identified to
demonstrate excellent purging power of 11a′ from a wide range
of starting levels: reducing 11a′ to 4% from as high as 21% and
reducing to 0.5% from a 2% starting level (Figure 4).
Scheme 4. Proposed degradation pathway from 11a to 12b
Scheme 3. Proposed reaction pathway for the formation of undesired
diastereomer 11a′
Under the optimized conditions, the level of undesired
diastereomer 11a′ could be controlled at an average of
approximately 3% over multiple development runs on a
decagram scale (Figure 3). Further investigation on the
temperature dependence of the stereochemical erosion revealed
L-alanine (2) racemized at an appreciable rate above 60 ºC while
the desired N-arylation of 3 was quite slow below 70 ºC. This
intrinsic reactivity difference posed an additional challenge to
minimize stereochemical erosion when scaling up the process in
a batch mode, because it would take a longer time to heat the
batch to the desired reaction temperature on a kilogram scale
compared to the laboratory runs. We envisioned two potential
Figure 4. Purging of undesired diastereomer 11a′ via isolation of
ammonium salt 11b
We suspected another contributing factor to the instability of
1
1a was the residual copper serving as a catalyst for the oxidative
solutions to circumvent this issue: charging
catalyst last to a reaction mixture preheated to 90
latter approach was deemed more practical to implement in a
L-alanine (2) or Cu O
2
degradation pathway. A survey of aqueous washes including
ammonium hydroxide or ammonium chloride during workup to
–
100 ºC. The
3

4
Tetrahedron
scavenge the copper led to a high loss of prod
A
uc
C
t in
C
t
E
he
P
a
T
qu
E
eo
D
us MAth
N
e c
U
or
S
re
C
sp
R
on
I
ding methyl ester of 11a improving the assay yield
P
T
layer. Evaluation of solid-based metal scavengers in THF
from 92% to 96% (entries 9 and 10).
1
5
identified SiliaMet® DMT as the best hit. At 40 wt %
scavenger loading relative to the mass of 11a, the residual copper
level could be reduced from >3000 ppm to <10 ppm. The
effective copper purging, in conjunction with the formation of the
corresponding ammonium salt 11b, significantly improved the
overall stability of free acid 11a. As shown in Figure 5, no
noticeable degradation was observed when a sample of 11b with
With all the previous optimization efforts, we were able to
develop
a
robust process amenable to kilogram-scale
manufacturing illustrated in Scheme 5. Chemoselective C−N
coupling between 4 and 5 under optimized conditions led to
compound 3 in 77% yield with minimized Br−I scrambling.
Subsequent coupling of 3 with L-alanine (2) under the optimized
conditions followed by copper scavenging and salt formation
afforded the ammonium salt 11b in 81% yield with high
stereochemical integrity and much improved stability.
Examination of reaction conditions for the final amidation step
8
ppm residual Cu was stored on benchtop over 7 days. It is
noteworthy that even copper-free 11a (< 3ppm) was found to be
unstable in our hands.
identified the best EDC/HOSu combination using NH in i-PrOH
3
to provide GDC-0077 API in 83% yield and >99.5% purity
ascertained by HPLC analysis.
Figure 5. Stability comparison of free acid 11a and
corresponding ammonium salt 11b
a
Table 3 Optimization of amide formation to produce 1
coupling
reagent
NH
3
source
b
c
conv
%)
yield
(%)
entry
SM
temp
(
(equiv)
1
2
3
4
5
6
7
8
9
11a
11b
11b
11b
11b
11b
11b
11b
11b
11b
CDI
NH
4
4
OH
OH
0
100
70
43
99
97
27
20
11
98
99
97
40
23
63
89
1
CDI
NH
0
T3P®
NH
NH
NH
NH
NH
NH
NH
3
3
3
3
3
3
3
/MeOH
/MeOH
/MeOH
/MeOH
/MeOH
/MeOH
/MeOH
/i-PrOH
0
Scheme 5. Synthesis of GDC-0077
HATU
0
EDC/HOBt
EDC/HOPy
EDC/NMI
EDC/DMAP
EDC/HOSu
EDC/HOSu
0 to 25
0 to 25
0 to 25
0 to 25
0 to 25
10
3
. Conclusion
In summary, we developed an efficient and robust process to
2
synthesize the GDC-0077 API featuring two consecutive Cu-
catalyzed C−N couplings in chemoselective and stereocontrolled
manner. The scalability and robustness of the developed process
was successfully demonstrated on multi-kilogram scale. Further
mechanistic studies are underway to understand the mechanism
2
92
96
1
0
NH
3
a
of Cu-catalyzed
. Experimental section
4.1. General
L-alanine racemization.
Reaction conditions: 11a or 11b (1 mmol), coupling reagent (2.0 equiv),
nucleophilic activator (1.0 equiv, used in the cases where EDC was the
4
3
coupling reagent), NH source (1.0 equiv), THF (0.24 M).
b
Determined by HPLC analysis of crude reaction mixture.
c
Quantitative assay yield based on HPLC analysis.
Unless stated otherwise, reactions were performed under an
ambient atmosphere of nitrogen in 20 mL vials sealed with
Teflon-lined caps. All solvents and commercially obtained
reagents were used as received, unless specified otherwise. Thin-
layer chromatography (TLC) was conducted with EMD silica gel
60 F254 pre-coated plates and visualized using UV light (254
nm). Flash column chromatography was performed with pre-
packed RediSep silica gel columns on a CombiFlash ISCO
With a robust process developed to prepare 11b in high purity,
we began evaluating reaction conditions for the final amidation
step (Table 3). Although initial experiment using CDI as the
coupling reagent yielded a clean reaction for acid 11a (entry 1),
the reaction starting with the ammonium salt 11b gave only 70%
conversion and 40% yield under identical conditions (entry 2)
due to the incompatibility between CDI and the ammonium ion.
Since it was highly desirable to use the isolated ammonium salt
system using MeOH in CH Cl2 (0−5% gradient) as eluent.
2
Analytical HPLC analyses were performed with an Agilent 1290
1
1
1b as the starting material to avoid an extra salt breaking step to
Infinity Series HPLC instrument. H NMR spectra were recorded
reform the corresponding acid 11a in situ, we next focused on
evaluating milder amidation conditions compatible with 11b
including T3P®, HATU, EDC in conjunction with nucleophilic
activators (entries 3−9). As a result, the reactions using EDC as
the dehydrating reagent and HOBt (entry 5) or HOSu (entry 9) as
the nucleophilic activator provided the best conversion and yield
on a Bruker 500 (at 500 MHz) and are reported relative to the
1
residual solvent peak (δ 2.50 for DMSO-d ). Data for H NMR
6
spectra are reported as follows: chemical shift (δ ppm),
1
3
multiplicity, coupling constant (Hz), and integration. C NMR
spectra were recorded on a Bruker 500 (at 126 MHz), and are
reported relative the residual solvent peak (δ 39.5 for DMSO-d ).
6
13
using NH in MeOH. Switching out the ammonia source to NH3
Data for C NMR spectra are reported in terms of chemical shift
3
in more sterically hindered i-PrOH eliminated the formation of
(δ ppm), multiplicity, and coupling constant (Hz) due to fluorine

5
splitting. IR spectra were recorded on a Bruke
A
r A
C
lp
C
ha
E
P
P
la
T
tin
E
u
D
m- MA
w
N
ith
U
E
S
tO
C
A
R
c
I
(
P
77.8 kg). The combined organic layers were
T
ATR spectrometer and are reported in frequency of absorption
washed with water (76.0 kg) and filtered through a pad of silica
gel (19.8 kg). The silica gel pad was rinsed with EtOAc (69.6
kg). The combined filtrates were concentrated to approximately
100 L under reduced pressure below 50 ºC and THF (146 kg)
was added. The resulting mixture was heated to 60 ºC until a
clear solution was obtained before it was concentrated to
approximately 100 L under reduced pressure below 50 ºC and
then cooled to 30 ºC. n-Heptane was charged (86.8 kg) and the
resulting mixture was stirred at 30 ºC for 2 h. The batch was
solvent-switched to n-heptane by three cycles of batch
concentration under reduced pressure below 35 ºC to
approximately 180 L and n-heptane addition (47.6 kg × 3). The
resulting suspension was cooled to 20 ºC, stirred for 12 h, and
filtered. The resulting solid was washed with n-heptane (64.0 kg)
and dried under reduced pressure at 45 ºC to afford 9-bromo-2-
−1
(
cm ). HRMS data was obtained on an LTQ Orbitrap Discovery
Thermo Fisher Scientific) at Genentech, Inc. Melting points
(
were measured by differential scanning calorimetry (DSC) and
were reported as onset temperature.
4
.2. Procedure for preparation of GDC-0077 (1)
9
-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
(6):
Into mixture of 8-bromo-2,3-
a
dihydrobenzo[f][1,4]oxazepin-5-amine hydrochloride (17.6 kg,
6
4
3.4 mol, 100 mol %) and 2-MeTHF (122 kg) were charged a
0% chloroacetaldehyde aqueous solution (16.4 kg, 132 mol %)
and water (10 kg). The mixture was heated to 40 ºC and aqueous
KHCO solution was charged. The reaction mixture was stirred at
3
4
5 ºC for 21 h. After the reaction was complete, the reaction
º
iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (25.3 kg,
8.7 wt %, 84% yield) as a light tan solid. mp 165 °C; H NMR
500 MHz, DMSO-d ) δ 8.22 (d, J = 8.7 Hz, 1H), 7.55 (s, 1H),
.31–7.23 (m, 2H), 4.48–4.39 (m, 4H); C NMR (126 MHz,
mixture was cooled to 20 C, stirred for 30 min, and filtered. The
resulting cake was rinsed with 2-MeTHF (33.0 kg) and the
combined filtrates were allowed to settle. The resulting organic
layer was washed with aqueous NaHSO3 solution (30 kg),
concentrated to approximately 26 L under reduced pressure
below 45 ºC. After the addition of DMF (25 kg), the mixture was
concentrated to approximately 26 L under reduced pressure
below 45 ºC. Water (154 kg) was charged at 40 ºC followed by
1
9
(
7
6
13
DMSO-d ) δ 156.0, 145.1, 131.4, 128.9, 125.8, 123.5, 122.4,
6
+
1
3
17.4, 83.7, 69.1, 49.8; HRMS calcd for C H BrIN O [M+H] :
11 9 2
90.8937, found 390.8949.
S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-
(
seeding
with
9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-
d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (3): 9-
bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
6.90 kg, 98.7 wt %, 17.4 mol, 100 mol %) was charged to a
reactor, followed by (S)-4-(difluoromethyl)oxazolidin-2-one
2.68 kg, 112 mol %), Cu(OAc) (0.653 kg, 20.6 mol %), and
Cs CO (11.7 kg, 206 mol %). The reactor was evacuated and
backfilled with N three times. 2-MeTHF (36.0 kg) and trans-
N,N-dimethylcyclohexane-1,2-diamine (0.764 kg, 30 mol %) was
then charged into the reactor. The reactor was evacuated and
backfilled with N three times. The reaction mixture was heated
to 78 ºC and stirred for 22 h. After the reaction was complete, a
0 wt % NaHSO aqueous solution (42.0 kg) was slowly added
while maintaining the internal temperature between 60–70 ºC.
The layers were separated at 65 ºC and the aqueous layer was
removed. The batch was solvent-switched to MeCN via a
constant volume distillation under reduced pressure at 60–70 ºC
by adding MeCN (62.3 kg). Water (14.1 kg) was added into the
reactor while maintaining the batch temperature between 60–70
d][1,4]oxazepine (1.20 kg). The mixture was stirred at 40 ºC for
another 1.5 h and cooled to 20 ºC. After stirring for 10 h at 20 ºC,
the suspension was filtered. The resulting solid was washed with
water twice (25 kg × 2) and dried under reduced pressure at 45 ºC
(
(
2
to
afford
9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-
1
2
3
d][1,4]oxazepine (16.3 kg, 97.5 wt %, 95% yield). mp 121 °C; H
2
NMR (500 MHz, DMSO-d ) δ 8.33 (d, J = 8.6 Hz, 1H), 7.34 (d, J
6
=
1.1 Hz, 1H), 7.28 (dd, J = 8.6, 2.1 Hz, 1H), 7.24 (d, J = 2.1 Hz,
13
1
H), 7.06 (d, J = 1.1 Hz, 1H), 4.50 – 4.39 (m, 4H); C NMR
2
(
126 MHz, DMSO-d ) δ 156.0, 142.9, 131.5, 129.1, 125.7, 123.6,
6
1
23.4, 121.7, 118.7, 69.4, 49.6; HRMS calcd for C H BrN O
11 10 2
+
2
4
[
M+H] : 264.9971, found 264.9976.
9
-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-
d][1,4]oxazepine (10b): Into solution of 9-bromo-5,6-
dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (16.3 kg, 97.5 wt
, 59.9 mol, 100 mol %) in DMF (78.0 kg) was added NIS (29.0
a
%
kg, 215 mol %) at 40 ºC. The reaction mixture was slowly heated
to 70 ºC and stirred for 6 h. After the reaction was complete, 10%
º
ºC. The suspension was cooled to 20 C at a rate of 0.5 ºC/min,
stirred for 18 h, and filtered. The resulting solid was washed with
a mixture of MeCN and water (50 kg, 44:56, w/w) and dried
under reduced pressure at 90 ºC to afford (S)-3-(9-bromo-5,6-
dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-
aqueous Na SO3 solution (78.0 kg) was charged at 45 ºC
2
followed by water (154 kg). The resulting suspension was stirred
at 45 ºC for 1 h and cooled to 20 ºC. After stirring at 20 ºC for 8
h, the suspension was filtered. The resulting solid was washed
with water (160 kg) and dried under reduced pressure at 45 ºC to
(
%
difluoromethyl)oxazolidin-2-one as a tan solid (5.85 kg, 91.9 wt
, 77% yield); mp 247 °C; H NMR (500 MHz, DMSO-d ) δ
6
1
afford
9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-
8
6
.26 (d, J = 8.7 Hz, 1H), 7.40 (s, 1H), 7.33–7.23 (m, 2H), 6.85–
.60 (m, 1H), 5.00 (ddd, J = 22.9, 8.7, 4.2 Hz, 1H), 4.66 – 4.55
d][1,4]oxazepine (29.7 kg, 100 wt %, 96% yield) as an off-white
1
solid. mp 180 °C; H NMR (500 MHz, DMSO-d ) δ 8.21 (d, J =
6
13
(m, 2H), 4.47 (q, J = 5.9, 4.3 Hz, 4H).; C NMR (126 MHz,
DMSO-d ) δ 156.3, 154.4, 139.3, 136.3, 131.6, 125.8, 123.4,
8
.7 Hz, 1H), 7.32–7.24 (m, 2H), 4.53–4.44 (m, 2H), 4.40–4.31
13
(m, 2H); C NMR (126 MHz, DMSO-d ) δ 156.5, 147.1, 131.2,
6
6
1
3
4
22.1, 117.8, 116.1–111.4 (m), 109.9, 69.2, 62.0, 55.8 (dd, J =
1
25.9, 123.4, 122.8, 117.2, 98.4, 89.7, 69.2, 53.5; HRMS calcd
+
+
1.0, 21.5 Hz), 50.1; HRMS calcd for C H BrF N O [M+H] :
for C H BrI N O [M+H] : 516.7904, found 516.7911.
15 13
2
3
3
11
8
2
2
00.0103, found 400.0134.
9
-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-
ammonium (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-
-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)
d][1,4]oxazepine (4): Into a solution of 9-bromo-2,3-diiodo-5,6-
dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (39.4 kg, 76.2 mol,
3
amino)propionate
dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-
difluoromethyl) oxazolidin-2-one 3 (3.96 kg, 91.9 wt %, 9.19
mol, 100 mol %) was charged to a reactor, followed by (S)-2-
aminopropanoic acid (2.49 kg, 307 mol %), anhydrous K PO
(11b):
(S)-3-(9-bromo-5,6-
1
00 mol %) in THF (180 kg) was added a solution of 2.0 M
EtMgBr in 2-MeTHF (44.0 kg, 120 mol %) at 10 ºC. The
reaction mixture was stirred at 10 ºC for 2 h. After the reaction
was complete, 5% aqueous HOAc (133 kg) was charged while
maintaining the batch temperature below 30 ºC. EtOAc (168 kg)
was charged and the resulting mixture was stirred at 20 ºC for 1
h. The layers were separated and the aqueous layer was extracted
(
3
4
(5.84 kg, 303 mol %), and DMSO (19.9 kg). The mixture was
sparged with N for 1 h and heated to 95 ºC. A slurry of Cu O
2
2
5

6
Tetrahedron
(
67.1 g, 5.16 mol %) in DMSO (2.21 kg) tha
A
t w
C
a
C
s p
E
re
P
-s
T
pa
E
rged MAdi
D
NU
hy
dro
S
b
C
en
R
zo
I
[f]imidazo[1,2-d][1,4]oxazepin-9-
P
T
with N for 30 min was then transferred to the reactor. The
reaction mixture was stirred at 95 ºC for 4 h. After the reaction
was complete, the reaction mixture was cooled to 20 ºC. DCM
yl)amino)propionate 17 (5.60 kg, 13.2 mol, 100 mol %) was
charged to a reactor, followed by N-hydroxysuccinimide (HOSu,
1.52 kg, 102 mol %) and THF (49.6 kg). The batch was sparged
with N for 40 min and cooled to 10 ºC. A 2 N solution of NH in
2
(37.3 kg) was added to the reactor, followed by water (24.2 kg).
2
3
The layers were separated and the organic layer was removed.
The aqueous layer was washed with DCM (26.6 kg) one more
i-PrOH (5.05 kg, 101 mol %) and N-(3-dimethylaminopropyl)-
N'-ethylcarbodiimide hydrochloride (EDC, 5.20 kg, 210 mol %)
were charged sequentially to the reactor. The reaction mixture
was stirred at 10 ºC for 20 h. After the reaction was complete, the
mixture was warmed up to 20 ºC and 15 wt % brine (33.7 kg)
was added. The layers were separated at 35 ºC and the aqueous
layer was removed. The organic layer was washed sequentially
with 15 wt % brine (2 × 16.9 kg) and a mixture of 15 wt % brine
time. THF (35.2 kg) and an aqueous NaHSO solution (19 wt %,
4
2
0.7 kg) were charged to the reactor sequentially. The layers
were separated and the aqueous layer was removed. The organic
layer was washed with 15 wt % brine (2 × 12 kg). SiliaMetS®
DMT (Silicycle Inc., 1.60 kg) was charged and the batch was
stirred at 25 ºC for 15 h and filtered to scavenge residual metal.
THF (24.8 kg) was used to rinse the filter. The combined filtrates
(8.97 kg) and 28.0–30.0 wt % NH OH (7.55 kg) and then filtered
4
were heated to 50 ºC. A 7 N solution of NH in MeOH (1.02 kg,
through a polishing filter unit. The filter unit was rinsed with
THF (5.05 kg). The combined filtrates were distilled under
reduced pressure at 50 ºC to approximately half of its original
volume. EtOH (8.90 kg) was charged at 50 ºC, followed by a
slurry of seeds (1, 27.1 g) in ethanol (0.340 kg). The resulting
suspension was stirred at 50 ºC for 30 min and solvent-switched
to EtOH via a constant volume distillation under reduced
pressure at 40–60 ºC by adding EtOH (39.9 kg). Water (0.379
kg) was added at 50 ºC. The suspension was cooled to 20 ºC,
stirred for 23 h, and filtered. The resulting solid was washed with
a 90:10 (w/w) mixture of EtOH and water (27.9 kg) and dried
under reduced pressure at 80 ºC to afford (S)-2-((2-((S)-4-
(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-
3
1
00 mol %) was added followed by a slurry of seeds (11b, 19.5
g) in THF (0.395 kg). The resulting suspension was stirred at 50
ºC for 2 h and a constant volume distillation was conducted at
4
0–60 ºC under reduced pressure to remove residual water by
adding anhydrous THF (60.1 kg). A 7 N solution of NH in
3
MeOH (1.02 kg, 100 mol %) was added. The suspension was
stirred at 50 ºC for 15 h and filtered. The resulting solid was
washed with THF (21.8 kg) and dried under reduced pressure at
2
5 ºC to afford ammonium (S)-2-((2-((S)-4-(difluoromethyl)-2-
oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-
d][1,4]oxazepin-9-yl)amino)propionate 11b as a beige solid (3.19
1
kg, 98.0 wt %, 81% yield, 99.7:0.3 dr). mp = 171 °C; H NMR
(
500 MHz, DMSO-d ) δ 7.97 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H),
dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-
6
6
.74–6.69 (m, 1H), 6.38 (dd, J = 9.0, 2.2 Hz, 1H), 6.07 (d, J = 2.2
yl)amino)propanamide 1 as a light pink solid (4.37 kg, 99.7 wt
%, 83% yield, 99.8:0.2 dr). mp 214 °C; H NMR (500 MHz,
1
Hz, 1H), 5.02–4.91 (m, 1H), 4.64–4.52 (m, 2H), 4.40–4.30 (m,
4
13
H), 3.63 (q, J = 6.1, 5.5 Hz, 1H), 1.27 (d, J = 6.7 Hz, 3H);
C
DMSO-d ) δ 8.01 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H),
6
NMR (126 MHz, DMSO-d ) δ 176.3, 157.3, 154.4, 150.2, 141.7,
7.18 (s, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.88–6.59 (m, 1H), 6.42
(dd, J = 8.8, 2.4 Hz, 1H), 6.16 (d, J = 7.1 Hz, 1H), 6.10 (d, J =
2.3 Hz, 1H), 5.02–4.90 (m, 1H), 4.64–4.53 (m, 2H), 4.35 (tdd, J
= 6.8, 3.9, 1.7 Hz, 4H), 3.78 (p, J = 6.9 Hz, 1H), 1.32 (d, J = 6.8
6
1
6
5
35.5, 130.8, 113.7 (t, J = 244.1 Hz), 109.0, 107.5, 105.8, 101.5,
8.6, 61.8, 55.8 (dd, J = 31.6, 21.1 Hz), 53.1 (d, J = 2.6 Hz),
+
0.0, 19.3; HRMS calcd for C H F N O [M+H] : 409.1318,
18
19
2
4
5
13
found 409.1318.
Hz, 3H); C NMR (126 MHz, DMSO-d ) δ 176.2, 157.2, 154.4,
6
1
1
49.9, 141.5, 135.6, 130.8, 116.8–110.8 (m), 109.3, 107.8, 106.9,
HPLC method for dr determination of compound 11a or 11b:
column, Waters XBridge C18 (150 × 3 mm, 3.5 µm);
temperature, 35 °C; flow rate, 1.0 mL/min; injection volume, 5
µL; detection, 215 nm; mobile phase A, 0.1% phosphoric acid in
water; mobile phase B, acetonitrile, gradient (20 min), 0–5 min =
02.0, 68.7, 61.8, 55.9 (dd, J = 31.2, 21.2 Hz), 52.6, 50.0, 19.2;
+
HRMS calcd for C H F N O [M+H] : 408.1478, found
4
18
20
2
5
4
08.1473.
HPLC method for dr determination of compound 1 (GDC-
2
1
–10% B, 5–10 min = hold 22% B, 10–15 min = 22–95% B, 15–
8 min = hold 95% B, 18–20 min = 2% B. tR of 11a = 8.633
0077): column, Ascentis Express C18 column (150 × 4.6 mm, 2.7
µm); temperature, 30 °C; flow rate, 1.0 mL/min; injection
volume, 5 µL; detection, 215 nm; mobile phase A, 5 mM
phosphate buffer pH=7; mobile phase B, methanol, gradient (30
min), 0–10 min = 2–50% B, 10–15 min = hold 50% B, 15–20
min = 50–85% B, 20–25 min = hold 85% B, 25–30 min = 2% B.
tR of 1 = 12.2 min, tR of 1′ (diastereomer) = 12.6 min.
min, tR of 11a′ = 9.108 min.
(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-
dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-
yl)amino)propanamide (GDC-0077, 1): Ammonium (S)-2-((2-
((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-

7
6
.
F. St-Jean, T. Remarchuk, R. Angelaud, D.E. Carrera, D.
ACCEPTED MANUSCRIPT
Beaudry, S. Malhotra, A. McClory, A. Kumar, G. Ohlenbusch, A.
Acknowledgments
Schuster, F. Gosselin. Org. Process Res. Dev. 23 (2019) ASAP,
DOI: 10.1021/acs.oprd.9b00050.
7
.
2
For Mg(OEt) promoted conversion of nitriles to amidines and its
We thank Dr. Haiming Zhang for proofreading the
manuscript, Dr. Mohammad Al-Sayah and Ms. Meenakshi Goel
for analytical support, and Dr. Sarah Robinson for collecting
HRMS data (Genentech, Inc.).
application to imidazole synthesis, see: M.E. Dalziel, J.A.
Deichert, D.E. Carrera, D. Beaudry, C. Han, H. Zhang, R.
Angelaud, Org. Lett. 20 (2018) 2624−2627.
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4844−14845.
D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J. Am. Chem. Soc. 120
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1
9
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Supplementary Material
(
0. a) N. Narendar, S. Velmathi, Tetrahedron Lett. 50 (2009)
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copies of H and C NMR spectra can be found in the online
version, at http://dx.doi.org.
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For chemoselective coupling of oxazolidinones with
1
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trimercaptotriazine (trithiocyanuric acid, TMT), and a versatile
metal scavenger for a variety of metals including ruthenium
catalysts and hindered Pd complexes.
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