Process Development of the HCV NS5B Site D Inhibitor MK-8876

Article abstract of DOI:10.1021/acs.oprd.5b00405

We describe the route development and multikilogram-scale synthesis of an HCV NS5B site D inhibitor, MK-8876. The key topics covered are (1) process improvement of the two main fragments; (2) optimization of the initially troublesome penultimate step, a key bis(boronic acid) (BBA)-based borylation; (3) process development of the final Suzuki-Miyaura coupling; and (4) control of the drug substance form. These efforts culminated in a 28 kg delivery of the desired active pharmaceutical ingredient.

Full text of DOI:10.1021/acs.oprd.5b00405

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Full Paper
Process Development of the HCV NS5b-site D Inhibitor MK-8876
Michael James Williams, Qinghao Chen, Lorenzo Codan, Renee K. Dermenjian, Spencer
D. Dreher, Andrew William Gibson, Xianliang He, Yan Jin, Stephen Philip Keen, Alfred
Lee, David Lieberman, Wei Lin, Guiquan Liu, Mark McLaughlin, Mikhail Reibarkh,
Jeremy P. Scott, Sophie Strickfuss, Lushi Tan, Richard J. Varsolona, and Feng Wen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00405 • Publication Date (Web): 25 Jan 2016
Downloaded from http://pubs.acs.org on January 26, 2016
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Process Development of the HCV NS5b-
site D Inhibitor MK-8876
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Michael J. Williams*,†, Qinghao Chen*,†, Lorenzo Codan,ᶲ Renee K. Dermenjian,† Spencer
Dreher,† Andrew W. Gibson,‡ , Xianliang He,§ Yan Jin,† Stephen P. Keen,‡ Alfred Y. Lee,† David R.
Lieberman,‡ Wei Lin,§ Guiquan Liu,§ Mark McLaughlin,† Mikhail Reibarkh,† Jeremy P. Scott,‡
Sophie Strickfuss,‡ Lushi Tan,† Richard J. Varsolona,† and Feng Wen§
† Department of Process and Analytical Chemistry, Merck Research Laboratories, Rahway,
New Jersey 07065, United States of America
‡ Department of Process Chemistry, Merck Sharp and Dohme Ltd., Hertford Road,
Hoddesdon, Hertfordshire, EN11 9BU, United Kingdom
ᶲ Werthenstein BioPharma GmbH (MSD Switzerland), Industrie Nord 1, CH-6105 Schachen,
Switzerland
§ WuXi AppTec Co., Ltd., No. 1 Building, #288 FuTe ZhongLu, WaiGaoQiao Free Trade
Zone, Shanghai 200131, China
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Abstract:
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We describe the route development and multi-kilogram scale synthesis of an HCV NS5b site
D inhibitor, MK-8876. The key topics covered are: 1) process improvement of the two main
fragments; 2) optimization of the initially troublesome penultimate step, a key bis-boronic acid
(BBA) based borylation; 3) process development of the final Suzuki-Miyaura coupling; 4) control
of the drug substance form. These efforts culminated in a 28 kg delivery of the desired API.
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KEYWORDS: Pd-catalyzed borylation, bis-boronic acid, Suzuki-Miyaura coupling, Buchwald biaryl
precatalyst, DoE design, High-throughput experimentation
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Introduction:
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Hepatitis C virus (HCV) is a leading cause of chronic liver disease, with an estimated 130-170
million people infected globally. This disease has a high degree of genetic heterogeneity and
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can be classified into six major genotypes that have distinct geographic distributions.
A
compelling medical need exists for new oral therapeutic agents with improved efficacy and
tolerability that inhibit the virus across disease genotypes.1 MK-8876 (1) is a small molecule
non-nucleoside inhibitor developed to target the Site D binding pocket of NS5B polymerase that
exhibited pan-genotypic activity in in vitro studies.2 The discovery synthesis of compound 1
provided a convergent route to MK-8876 via two key intermediates: chloroindolopyridine 2
and boronate 3 (Scheme 1). Chloroindolopyridine 2 was synthesized in four steps from 4-
fluoroindole (4), and boronate 3 was derived from 2-hydroxybenzeneacetic acid (5) (Scheme 2).
Four key areas were defined as critical points of optimization to ensure multi-kilogram
scalability and delivery of the drug substance:
(1) The route to chloroindolopyridine 2 progressed through the unstable indoloboronic
acid 7; further process development would be necessary to support the handling
times required on scale.
(2) Benzofuran 19 was synthesized via a long linear sequence with multiple
chromatographic separations. The Claisen condensation and benzofuran formation,
in particular, were targets for optimization.
(3) The convergent endgame chemistry, specifically the borylation of bromobenzofuran
19, suffered from a poor yield. Further, the final Suzuki-Miyaura coupling utilized
dioxane as the reaction solvent, leading to both operational and safety concerns.
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(4) A scalable procedure to access the desired drug substance crystal form of MK-8876
(1) was necessary.
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Scheme 1: Retrosynthetic analysis of MK-8876 (1)
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Scheme 2: Discovery Route to MK-8876 (1)
HO
Boc
N
Boc
N
H
H
N
PdCl2(PPh3)2 (5 mol%)
Boc2O, DMAP
LDA, THF, -78 °C;
N
B(OH)2
THF; SiO2
B(OiPr)3; SiO2
pyridine 9
NaHCO3 (aq)
dioxane, 90 °C
70% yield
N
96% yield
64% yield
Cl
F
F
F
F
10
6
7
4
Cs2CO3, ClCH2I,
DMF
OH
OH
I2, Na2CO3
79% yield
THF, H2O
80% yield
Cl
N
I
Cl
N
O
9
8
N
N
Cl
F
2
F
COCl
O
Br
Br
Br
TBSCl, imidazole
13
F
TBATB, MeOH;
CO2H
OH
CO2Me
OTBS
CO2Me
CO2Me
DCM; SiO2
96% yield
LDA, -78 °C
70% yield
SiO2
90% yield
OTBS
OH
5
12
14
11
1) TBAF, THF;
SiO2
97% yield
2) HCl, acetone;
reflux; SiO2
71% yield
1) Fe0, NH4Cl
THF, MeOH;
CO2Me
CO2Me
CO2Me
HNO3, CHCl3
Br
Br
Br
F
F
F
-10 °C
O
O
17
O
reflux; SiO2
79% yield
2) MsCl, pyr,
DCM, 0 °C
88% yield
MsHN
O2N
70% yield
15
16
1) LiOH, dioxane, reflux
97% yield
2) EDC, HOBt,
MeNH3Cl, NEt3, DMF
96% yield
Me
NH
1) Pd(dppf)Cl2, B2(pin)2,
KOAc, DMAc, H2O
56% yield
O
O
MeI, K2CO3
KI, DMF
CO2NHMe
CO2NHMe
N
Br
Br
N
F
F
F
94% yield
Ms
Ms
2) Pd2(dba)3, Xphos,
chloroindolopyridine 2
K3PO4, dioxane, H2O
78% yield
O
O
N
N
O
MsHN
Me
Me
18
19
F
MK-8876 (1)
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Results and Discussion:
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Optimization of indole 2 synthesis
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The original bond disconnections toward the preparation of indole 2 and benzofuran 19
were deemed suitable for further reaction development. We intended to eliminate all
chromatographic purifications (7 out of 16 steps) and identify through-processing opportunities
to increase yield without sacrificing purity. We focused our efforts initially on: 1) the one-step
preparation of pyridine 9 and 2) its subsequent coupling with fluoroboronic acid 7 to afford
indolopyridine 2 (Scheme 3). Altering the base from Na2CO3 to K2CO3 and running the
iodination reaction in pure water as opposed to aqueous THF led to improved performance and
isolation of pyridine 8:3 elimination of THF simplified the workup for this step and iodide 9 was
isolated in 89% yield by crystallization from n-heptane. The coupling partner of iodide 9,
boronic acid 7, was initially isolated in a modest 64% yield via deprotonation of indole 6 and
quench with triisopropyl borate.4 We surmised that the moderate yield of boronic acid 7 was a
result of decomposition during processing, not a low yielding borylation reaction.5 Indeed, the
addition of triisopropyl borate to a mixture of LDA and indole 6, followed by acidic workup,
provided a solution of indoleboronic acid 7 in quantitative yield. Furthermore, the crude
mixture obtained from Boc protection of indole 4 could be used in the borylation without
impact on yield or purity.
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Scheme 3: Preparation of Indole 2
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With efficient processes to boronic acid 7 and iodide 9 in hand, we turned our attention to
the subsequent Suzuki-Miyaura coupling.6 During the coupling, the unprotected indole 10 is
formed under the reaction conditions rather than the expected N-Boc indole. While the Boc
group of indole 7 is stable under basic conditions, we hypothesize that the presence of a
neighboring phenol functionality in pyridine 10 allows the Boc group to migrate7 from N to O
followed by carbonate saponification. The original coupling process provided product 10 in 77%
isolated yield utilizing 1,4-dioxane, an undesirable solvent for large scale synthesis.8 THF was
found to be an acceptable replacement, but due to the instability of boronic acid 7 during
distillative solvent exchange, the reaction solvent was limited only to THF or THF mixtures. We,
therefore, focused exclusively on THF with aqueous base rather than introducing an additional
organic co-solvent to minimize the total reaction volume. Under the initial conditions (Table 1,
entry 1), indole 6, the result of protiodeborylation, was observed as the main byproduct.9 We
examined a series of common inorganic bases with a range of pKa’s (Table 1, entries 2, 5, and 6)
using 5 mol% Pd(OAc)2 and 10 mol% PPh3. KHCO3 was identified as the optimal base, providing
the desired product in 85% assay yield; the formation of indole 6 was correspondingly reduced
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by more than 50% from >10% LCAP10 to 5% LCAP. Higher assay yield of product 10 was
achieved by employing Pd(OAc)2 instead of Pd2dba3 or Cl2Pd(PPh3)2 (entries 5 vs. 1 and 9) for
assay yield of product. In addition to PPh3, 48 monodentate and bidentate phosphine ligands
were surveyed in this chemistry. SPhos and the water soluble sulfonylated SPhos11 (NaSO3-
SPhos) performed comparably as ligands in the Suzuki reaction.12 However, the cost savings
associated with reduction in Pd loading were offset by the higher ligand cost and long lead
time. Therefore, the Pd(OAc)2/PPh3 system was utilized to prepare indole 10 in 85% assay yield
and 78% isolated yield after crystallization from CH2Cl2 and MTBE. Finally, aminal formation
from indole 10 using ClCH2I and Cs2CO3 in DMF provided chloroindolopyridine 2 in 95% assay
yield and 85% isolated yield.13
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Table 1: Screening results from the Suzuki-Miyaura coupling to generate indolopyridine 10
Entrya Pd salt (mol%)
Ligand (mol%)
None
Base
NaHCO3
KHCO3
KHCO3
KHCO3
NaHCO3
KF
10b
54
85
74
81
69
50
64
75
57
6b
24
5
Assay yield of 10
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2
3
4
5
6
7
8
9
Cl2Pd(PPh3)2 (5%)
Pd(OAc)2 (5%)
Pd(OAc)2 (2%)
Pd(OAc)2 (3%)
Pd(OAc)2 (5%)
Pd(OAc)2 (5%)
Pd2dba3 (2.5%)
Pd2dba3 (2.5%)
Pd2dba3 (2.5%)
N.D.
85%
52%
71%
N.D.
N.D.
N.D.
N.D.
N.D.
PPh3 (10%)
PPh3(4%)
15
10
19
30
18
14
20
PPh3 (6%)
PPh3 (10%)
PPh3 (10%)
PPh3 (10%)
PPh3 (10%)
PPh3 (10%)
K2CO3
KHCO3
NaHCO3
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Pd(OAc)2 (2%)
Pd(OAc)2 (2%)
NaSO3-SPhos
(5%)
Cs2CO3
Na2CO3
78
78
11
13
83%
85%
SPhos (5%)
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a: General coupling conditions: 1.0 equiv. 9, 1.2 equiv. 7, 3 equiv. base, THF (16 vols), water (2
vols), 70 °C, 12 h. Pd catalyst and ligand are as specified in Table 1.
b: LCAP of compound
Optimization of the synthesis of the benzofuran (19)
Scheme 4: Preparation of benzofuran 19
F
Cl
MeO
O
MeO
O
F
13
O
OMe
Br
OMe
TBSCl, Imidazole,
TBATB, MeOH,
30-35 °C, 88%
Br
Br
O
O
LHMDS,
THF, -60 °C
CH2Cl2, rt,
100% AY
OH
OH
O
OTBS
OTBS
20
11
12
14
aq. HCl,
acetone,
45 °C
MeO
O
F
CO2Me
CO2Me
CO2Me
Fe0, NH4Cl,
HNO3, TFA,
50 °C, 90%
Br
Br
O2N
65% from
12
Br
Br
F
F
F
O
aq. MeOH, THF,
82%
O
H2N
O
O
OH
21
22
16
15
MsCl, pyridine,
CH2Cl2, 30 °C,
93%
O
CO2Me
CO2H
MeNH3Cl, EDC,
HOBt, NEt3,
NHMe
CO2Me
Br
Br
LiOH, aq. THF,
CH3I, K2CO3,
DMF, 40 °C
Br
Br
MsHN
F
F
F
Ms
Ms
F
O
O
Ms
70 °C,
97% from 17
N
N
O
DMF, 30 °C, 89%
O
N
Me
Me
Me
17
23
24
19
We next turned our attention to the synthesis of bromide 19, the benzofuran core of MK-
8876. Bromination of methyl ester 20 with tetra-n-butylammonium tribromide (TBATB)14 in
MeOH reproducibly achieved >90% solution assay yield and afforded 11 in 88% yield after
crystallization from MTBE and n-heptane.15 The next four steps from phenol 11 to benzofuran
15 were identified as a potential through-process sequence. TBS protection of phenol 11
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proceeded in quantitative yield under standard conditions, and the resultant crude THF solution
of TBS ether 12 was enolized using LHMDS and acylated with p-fluorobenzoyl chloride (13) to
afford β-ketoester 14 in 87 LCAP. Deprotection of the resultant TBS ether 14 under basic TBAF
conditions generated up to 20% of an unidentified impurity, but this impurity could be avoided
by deprotection under acidic conditions. Aqueous HCl was charged as part of the aqueous
workup for ketoester 21 and up to 20% benzofuran 15 was observed during the distillative
solvent exchange from MTBE/THF into acetone. Additional concentrated HCl was charged to
complete the cyclization. Benzofuran 15 was purified by crystallization from CH2Cl2/MeOH in
65% yield from phenol 11 (average of 90% yield per step).
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Nitration of benzofuran 15 in TFA at 50 °C provided nitroarene 16 in 90% yield, a 20%
improvement over the original process.16 This nitration process had no strongly exothermic
events up to 360 °C by DSC measurement, well above the reaction temperature of 50 °C.17 The
nitroarene was reduced to the corresponding aniline 22 using iron powder and aqueous NH4Cl
in a mixture of THF and MeOH in 82% isolated yield.18 Initially, we conducted this reaction by
charging Fe powder in a single portion to the solution of nitroarene 16 at 20-25 °C, but a
delayed exotherm was observed under these conditions. Reaction calorimetry measurements
of this single charge process revealed an adiabatic temperature rise of 13 °C with a maximum
batch temperature of 75 °C. Although this exotherm was expected to fall comfortably within
the cooling capacity of our production equipment, we altered the process to add the iron
powder portion-wise to the remainder of the reactants at 60-65 °C as an additional safety
control.
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Mono-mesylation of aniline 22 was found to be dependent on the identity and quantity of
the amine base used in the reaction. Using 5 equivalents of trialkylamines, such as NEt3 and
DIPEA, gave only the bis-mesylated product, while the less basic pyridine gave predominantly
the mesylated benzofuran 17.19 With compound 17 in hand, sulfonamide 23 was obtained after
methylation. Subsequent saponification with LiOH afforded acid 24. Amide coupling of acid 24
with methylamine hydrochloride salt under standard EDC/HOBt20 conditions completed the
synthesis of 19.21 The yield of the three step sequence from sulfonamide 17 to amide 19 was
improved from 77% to 86%.
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Endgame borylation development
Scheme 5: Borylation, Suzuki-Miyaura coupling, and form change
The borylation of benzofuran 19 proved low yielding using the discovery chemistry
conditions (Scheme 2); as such, alternative conditions were sought to increase yield and,
ultimately, throughput. Initial attempts to generate boronate ester 3 via halogen-metal
exchange and quench with methoxyboronic acid pinacol ester proved unsuccessful because of
failure to generate the requisite anion.22 Concurrently, efforts were undertaken toward
improving the palladium-catalyzed borylation with bispinacolatodiboron (B2pin2) via high
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throughput experimentation (HTE). While yield improvements were observed under a variety
of conditions, des-bromoarene 28 was still present as a large contaminant (~20-30%). We
hypothesized that both approaches proved sub-optimal due to the steric hindrance about the
aryl bromide conferred by the ortho sulfonamide group. Therefore, we evaluated the much
smaller bisboronic acid (25) as an alternative borylation reagent. Gratifyingly, a significant
increase in assay yield of arylboronic acid 27, with concomitant decrease in the level of des-
bromoarene 28, was accomplished utilizing this reagent.23 Early screening efforts identified
conditions that utilized a 2nd generation Buchwald Cy3P pre-catalyst (26) and a base at elevated
temperature in methanol. Further studies revealed several key reaction parameters: 1)
diisopropylethylamine (3.0 equiv.) as base provided the fastest reaction rate and highest
yield24; 2) excess bisboronic acid (1.5 equiv.) was necessary to achieve complete conversion;
and 3) exogenous sub-stoichiometric PCy3 suppressed the formation of des-bromoarene 28 and
prevented catalyst death, but also served to inhibit the reaction.25
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To fully optimize the yield for the borylation step and minimize the Pd charge, a 3-factor
design of experiment (DoE) study was constructed. The impact of the following three factors
was evaluated: 1) pre-catalyst charge (0.25-0.75 mol %, with an equimolar charge of PCy3), 2)
temperature (55-65 °C for 6 h), and 3) concentration (7–13 volumes methanol).26 The reaction
temperature and concentration were identified as the significant factors from the study. The
borylation yield was maximized at high temperature and high dilution (Figures 1). Surprisingly,
catalyst loading was found not to be significant within the tested parameters, and no single
factor appeared to have a significant effect on the formation of des-bromoarene 28.
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Figure 1: Borylation reaction DoE results for Aryl boronic acid 27
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(i) Cube plot and (ii) Response Surface Plot
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Building on the results from above, the addition of precatalyst 26 to a refluxing mixture of
aryl bromide 19, bisboronic acid (25), and triethylamine afforded reproducible and consistently
high yields with minimal formation of des-bromoarene 28. To alleviate the heightened safety
concerns with this elevated temperature charge of catalyst, calorimetry experiments were
conducted to determine heat of reaction and adiabatic temperature rise.27 The pre-catalyst
was added to the complete reaction mixture at 60 °C and then aged at this temperature.28 The
heat of reaction was -248 kJ/mol, but with a large methanol heat sink, the adiabatic
temperature rise was only 10.5 K over 3 h. Further safety testing revealed no significant
concern to conducting this operation under the stated conditions.29
With the key borylation conditions developed, isolation of arylboronic acid 27 was
accomplished directly from the reaction mixture with the addition of water, albeit without
rejection of des-bromoarene 28. While final isolation conditions were being developed,
subsequent downstream development efforts revealed that experimental batches of API
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contained unacceptably high levels of palladium for use in clinical trials. MP-TMT resin30 was
identified from a multi-resin screen as the optimal treatment for the borylation stream,
significantly reducing palladium with minimal product loss.31 In the finalized process, methanol
and DIPEA were added to a mixture of arylbromide 19 and bisboronic acid (25), and the
resulting slurry was heated to 60 °C. The pre-catalyst (0.5 mol %)32 was then charged as a
solution in methanol, and the reaction mixture heated to reflux (63-65 °C). The reaction was
complete after 1 h with 93.9% desired boronic acid 27, 5.1% des-bromoarene 28, and 0.5%
starting bromide 19. The batch was cooled to room temperature and treated with MP-TMT
resin (50 wt%).33 The resulting solution was concentrated and boronic acid 27 was crystallized
with the addition of water. Boronic acid 27 was isolated in 88% yield (27.5 kg) with 6.3% of des-
bromoarene 28 and 102 ppm palladium34 and 93 ppm phosphorus.35
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Suzuki-Miyaura coupling and final solid form development
The previous conditions for the final Suzuki-Miyaura coupling had employed arylboronate
ester 3 as substrate and 1,4-dioxane as the solvent. Incorporation of boronic acid 27 as
reaction partner required new Suzuki-Miyaura coupling conditions.36 HTE efforts led to
identification of SPhos Buchwald 2nd generation precatalyst 29 as the optimal catalyst.37 The
reaction was carried out in acetonitrile with aqueous K3PO4 (2.5 M), providing the desired
product in excellent yield with minimal formation of protiodeborylation product 28. Upon
scaling these conditions, the desired product was observed to crystallize directly from the
reaction mixture. Interestingly, the crystallized product preferentially migrated into the
acetonitrile phase of the biphasic mixture on separation. This phenomenon simplified
isolation/purification because the solids could be easily collected in excellent yield with
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complete purge of des-bromoarene 28.38 However, while this process was conducted in glass
reactors with 99% isolated yield, the isolation was not suitable for larger fixed equipment due
to the expected poorer visible indication of phase separation.
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Figure 2: Powder X-Ray Diffraction Patterns of MK-8876 Forms 1 (red), 2 (blue) and 3 (black).
MK-8876 was shown to exist as three non-solvated distinct polymorphic forms (Forms 1, 2
and 339 – See Figure 2) of which Form 1 is preferred at or below 85 °C.40 Although the Suzuki-
Miyaura coupling process in acetonitrile produced MK-8876 in high yield and purity, the high
reaction temperature coupled with the reactive crystallization generated undesired Form 2
(Figure 2). To streamline isolation of the desired form, we sought to combine the Suzuki-
Miyaura coupling and form change into a single step. THF and water mixtures conferred unique
solubility properties on MK-887641 which were utilized to generate a high yielding, volume
efficient crystallization process on multi-kilogram scale.42 Replacement of acetonitrile with THF
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(10 volumes) as the reaction solvent for the Suzuki-Miyaura coupling provided a successful
solution: conversion to the desired product occurred in essentially quantitative yield, and
importantly, no product crystallized from the reaction mixture after cooling to room
temperature. The aqueous layer was removed, and the organic layer washed with 5 wt%
aqueous sodium chloride solution to afford the desired product in 99% solution yield.43 2-
Propanol was identified as the optimal anti-solvent for the crystallization of MK-8876 Form 1.44
A new isolation process was developed by first concentrating the post work-up solution to 6
volumes while reducing the water content (11-19 wt%) via distillation, heating the
concentrated mixture to 40-50 °C, seeding, and finally charging anti-solvent slowly (2-propanol
– 7 volumes). The resulting mixture was aged for several hours (40-50 °C), ramp cooled (20 °C),
and the solids isolated via filtration. Des-bromoarene 28 was completely purged during
crystallization. Based upon these experimental findings, a single 25 kg Suzuki-Miyaura reaction
was conducted in THF to afford the desired product in 98% solution assay yield containing 5% of
des-bromoarene 2845 and 1.5% of chloropyridine 4. Isolation as described above provided MK-
8876 Form 1 in 86% yield (28.6 kg, 99.0 wt%) with just 18 ppm Pd. Interestingly, during
development of the final crystallization process, a stable heterosolvate of MK-8876 (mixed
mono-THF hemihydrate solvate) was encountered. A process phase map was generated to
assess the relative stability of the solvated form in different water and solvent activities in order
to identify a design space to manufacture Form 1 (Figure 4). Form 1 was observed to be the
thermodynamically preferred phase at either elevated temperature or elevated 2-propanol
composition. At room temperature and low 2-propanol composition, there is a minor regime in
the phase map where the heterosolvate is favoured (Figure 4, highlighted in red). The
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heterosolvate can be converted to Form1 by either raising the temperature or adding 2-
propanol.
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Figure 3: Solubility of MK-8876 Form 1 in THF-H2O Mixtures at 25 °C and 50 °C.
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Solution Composition of MK-8876 Form 1 in THF as a
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Weight % water in solution composition
Figure 4: MK-8876 Phase Map in THF-H2O-2-Propanol Mixtures at 20 °C (left) and 45 °C (right).
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A recent related publication by these laboratories46 focused specifically on the identification
and control of potential mutagenic impurities (PMI’s)/ mutagenic impurities (MI’s) within the
MK-8876 process. In our initial in silico PMI/MI screening, seven reagents/intermediates were
flagged as necessary to understand and control: carbazole; arylboronic acid 27; bis-boronic acid
(25); EDC; MeI; ClCH2I; and indoleboronic acid 7. By conducting thorough analytical testing of
stage gate intermediates along the process, full understanding and control of these impurities
was obtained. Further, the experimental purge data facilitated the comparison with predicted
impurity removal using the purge factor approach.47
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Conclusion:
We have described the chemistry utilized in two GMP deliveries for the production of MK-8876
(1) on multi-kilogram scale. Indolopyridine 2 was prepared from 4-fluoroindole (4) in 5 steps
and an overall yield of 57%. Development and implementation of a through-process for the
formation of unstable boronic acid 7, combined with an optimized Suzuki-Miyaura coupling,
served to maximize the sequence yield. Benzofuran 19 was isolated in 33% yield via a 10-step
linear procedure. Significant yield improvements were achieved by Claisen condensation base
optimization and a through-process procedure yielding intermediate 15 in 65% isolated yield.
HTE enabled the identification of bisboronic acid (25) as the optimal borylation reagent,
providing a significant yield increase with concomitant reduction of undesired des-bromoarene
28. An optimized final Suzuki-Miyaura coupling provided the desired product 1 in nearly
quantitative yield. Finally, two API crystallization processes were developed to obtain the pure
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desired phase while maximizing purity and yield. With these myriad improvements, the largest
delivery yielded more than 28 kg of MK-8876.
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Experimental:
All reactions were carried out under a nitrogen atmosphere unless otherwise stated. All
solvents and reagents were purchased from commercial sources and were used without further
1
purification. H, 13C, and 19F NMR chemical shifts were reported relative to residual proton
solvent peaks. All yields are corrected for purity and determined by reverse phase HPLC assay
using purified standards.
Methyl 2-(5-bromo-2-hydroxyphenyl)acetate (11): Tetra-n-butylammonium bromide (33.7 kg,
104.6 mol, 0.35 equiv) was dissolved in MeCN (126.2 kg), and bromine (16.8 kg, 105.1 mol, 0.35
equiv) was added and aged at room temperature for 1 hour. Tetra-n-butylammonium
tribromide (TBATB , 100.7 kg, 208.8 mol, 0.70 equiv) was added to the TBATB solution and aged
at room temperature for 1 h. The resultant TBATB solution was diluted with MeOH (63.0 kg).
The TBATB solution was slowly added to the solution of methyl ester 20 (49.5 kg, 298.1 mol, 1.0
equiv) in MeOH (42 kg) and MeCN (82.6 kg) at 30-35 °C. The mixture was aged at 30-35 °C for 5
h to achieve 99.8% conversion. The mixture was cooled to room temperature and 20 wt%
aqueous NaHSO3 (261.0 kg) was added. The product was extracted with MTBE (253 kg). The
organic layer was concentrated to ~100 L and diluted with a mixture of MTBE (497.0 kg) and
water (348.0 kg). The mixture was heated to 35 °C for 2 h and cooled to 20 °C. The layers were
separated and the organic layer was washed successively with water (4x266 kg). The organic
layer was concentrated to ~100 L and diluted with MTBE (30 kg). Bromide 11 was crystallized by
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the addition of n-heptane (374 kg) over 2 h. The mixture was concentrated to ~425 L, aged at
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30-35 °C for 9 h, then aged at 0-5 °C for 3 h. The product was isolated by filtration and dried
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under vacuum at 30-40 °C to give 65.8 kg (97.5 wt%, 98.0 LCAP, 261.8 mol, 87.8% yield). H
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NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.31 (s, 1 H), 7.26-7.23 (m, 1H), 6.76 (d, J = 8.8 Hz, 2H),
3.57 (s, 3H), 3.34 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 171.7, 155.4, 133.9, 131.1, 124.5,
117.3, 110.1, 52.1, 35.1; mp 81.1 °C.
Methyl 2-(5-bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetate (12): Bromide 11 (64.1 kg,
97.5 wt%, 255 mol, 1.0 equiv), imidazole (28.8 kg, 423 mol, 1.65 equiv) were dissolved in CH2Cl2
(389.6 kg) at room temperature. To this solution was added a solution of TBSCl (50.6 kg, 335.7
mol, 1.3 equiv) in CH2Cl2 (144.4 kg) over 3 hours while maintaining internal temperature of 20-
25 °C. The mixture was stirred at room temperature for 5 h. The batch was cooled to 15-20 °C
and water (326 kg) was added over 2 h while maintaining internal temperature of 15-25 °C. The
mixture was stirred and the layers were separated. The organic layer was washed sucessively
with water (328 kg, 322 kg, 334 kg). The CH2Cl2 was replaced with THF via distillation to give a
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THF solution of TBS ether 12 (384.4 kg, 24.4 wt%, 261 mol, 96.5 LCAP) in 100% assay yield. H
NMR (400 MHz, DMSO-d6) δ 7.22-7.21 (d, J = 2.4 Hz, 1H), 7.21-7.10 (dd, J = 8.8, 2.4 Hz, 1H),
6.61-6.59 (d, J = 8.8 Hz, 1H), 3.40 (s, 2H), 3.38 (s, 3H), 0.73(s, 9H), 0.1 (s, 6H); 13C NMR (100
MHz, DMSO-d6) δ 173.6, 155.7, 136.7, 133.7, 130.7, 122.6, 114.9, 54.3, 37.8, 28.1, 20.5, -1.9;
HRMS: m/z calcd for C15H23BrO3Si: [M+H]+ 359.0673; found 359.0656.
Methyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (15): The THF solution of TBS
ether 12 (384.4 kg, 24.4 wt%, 261 mol, 1.02 equiv) was charged to a vessel via a line filter. THF
(720 kg) was added to this vessel and the solution was cooled to -60 °C. LHMDS (480.6 kg, 1 M
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in THF, 574.4 mol, 2.2 equiv) was added over 3 h while maintaining internal temperature
between -70 and -50 °C. The mixture was aged at -60 °C for 1 h and acid chloride 13 (46.2 kg,
291.3 mol, 1.14 equiv) was added while maintaining the internal temperature between -70 and
-50 °C and the batch was aged at -60 °C for 1 h. The batch was warmed to -20 °C and quenched
by the addition of 50 wt% HOAc in THF (161.2 kg solution) over 1 h. The batch was warmed to
room temperature and aged for 1 h. Water (484 kg) was added and the layers were separated.
The organic layer was concentrated to around 300 L and diluted with MTBE (1133 kg). This
solution was washed successively with 0.5 M aqueous HCl (2x472 kg) and water (514 kg). The
MTBE/THF was replaced by acetone via distillation to give an 890 L acetone solution.
Concentrated HCl (263.1 kg) was added and the mixture was aged at room temperature for 20
h. The solution was concentrated to ~500 L and additional concentrated HCl (441.5 kg) was
added. The mixture was aged at 45 °C for 2 h. The mixture was cooled to room temperature
and diluted with MeOH (362 kg). The slurry was filtered and washed with MeOH (408 kg) to
give crude benzofuran 15 (136.7 kg wet cake, 91.8 LCAP). The wet cake was dissolved in CH2Cl2
(1750 kg) and washed with water (4x500 kg). The organic layer was concentrated to ~200 L and
cooled to 15-20 °C. MeOH (1600 kg) was charged and the mixture was aged at 15-20 °C for 4 h.
The slurry was filtered, washed with MeOH (251 kg), and dried at 40-45 °C under vacuum to
give benzofuran 15 (58.8 kg, 97.9 wt%, 165 mol, 99.5 LCAP) in 64.7% yield from TBS ether 12.
1H NMR (400 MHz, DMSO-d6) δ 8.14-8.07 (m, 3H), 7.74 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.0 Hz,
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1H), 7.42 (ap. t, J = 8.8 Hz, 2H), 3.892 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 162.8 (d, JC-F
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247.9 Hz), 162.3, 159.7, 151.4, 131.5, 131.4, 127.8, 124.2, 123.8, 116.2, 114.8 (d, JC-F = 21.9 Hz),
113.0, 107.2, 51.3; 19F NMR (376 MHz, DMSO-d6): δ 108.7; mp 146.7 °C.
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Methyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (16): Benzofuran 15
(58.7 kg, 97.9 wt%, 164.5 mol, 1.0 equiv) was dissolved in TFA (3160 kg) at 50 °C. While
maintaining internal temperature between 40 and 55 °C, nitric acid (11.6 kg, 184.1 mol, 1.1
equiv) was added. The mixture was aged at 50 °C for 1 h, cooled to 5 °C, and diluted with water
(648 kg) while maintaining internal temperature between 0 and 5 °C. The mixture was aged for
3 h and the batch was filtered. The wet cake was washed with water (460 kg, 465 kg, 280 kg) to
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give nitroarene 16 (110.3 kg, 52.8 wt%, 147.8 mol, 98.0 LCAP) in 89.8% yield. H NMR (400
MHz, DMSO-d6) δ 8.65 (s, 1H), 8.38 (s, 1H), 8.15-8.11 (m, 2H), 7.49-7.44 (ap. t, J = 8.8 Hz, 2H),
3.92 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.3 (d, JC-F = 249.3 Hz), 164.1, 162.8, 151.2,
147.1, 132.8, 131.7, 127.5, 124.7, 116.2 (d, JC-F = 21.9 Hz), 110.5, 108.9, 108.4, 52.7; 19F NMR
(376 MHz, DMSO-d6): δ 107.6; mp 200.9 °C.
Methyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (22): Nitroarene 16
(110.3 kg, 52.8 wt%, 147.8 mol, 1.0 equiv) and NH4Cl (49.3 kg, 921.7 mol, 6.2 equiv)) were
dissolved in a mixture of THF (608 kg), MeOH (371 kg), and water (172 kg) at 70 °C. Iron powder
(28.4 kg, 578.4 mol, 3.9 equiv) was added portion-wise while maintaining batch internal
temperature between 65 and 70 °C. The batch was aged for 2 h and cooled to 25-35 °C. Celite
(154.1 kg) was added and the mixture was agitated for 1 h. The batch was filtered and washed
with THF (708 kg). The filtrate was diluted with water (120 kg). The layers were separated and
the organic layer was concentrated to ~600 L and cooled to 10-20 °C. Water (610 kg) was added
and the batch was aged at 15 °C for 3 h. The batch was filtered, washed with water (193.2 kg),
and dried at 50-60 °C under vacuum to give aniline 22 (44.5 kg, 99.0 wt%, 121.0 mol, 99.2 LCAP)
in 81.9% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.01 (m, 2H), 7.92 (s, 1H), 7.39-7.34 (m,
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(d, JC-F = 21.9 Hz), 108.2, 106.3, 96.5, 52.2; 19F NMR (376 MHz, DMSO-d6): δ 109.9; HRMS: m/z
calcd for C16H11BrFNO3: [M+H]+ 363.9979; found 363.9975; mp 183.7 °C.
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Methyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (17):
Aniline 22 (44.2 kg, 99.0 wt%, 120.1 mol, 1.0 equiv) was dissolved in CH2Cl2 (532 kg) and
pyridine (48 kg, 607 mol, 5.1 equiv) at 30 °C. MsCl (24.0 kg, 210 mol, 1.7 equiv) was added over
2 h.The batch was aged at 30 °C for 20 h and diluted with water (333 kg). The mixture was aged
at 30 °C for 3 h and then diluted with 1 N aqueuous HCl (200 kg). The batch was concentrated
to ~560 L and adjusted to room temperature. The batch was filtered and washed with water (74
kg, 80 kg). The wet cake was dissolved in EtOAc (160 kg) at 45 °C and cooled to 5-10 °C. The
batch was filtered, washed with EtOAc (110 kg), and dried at 50-60 °C under vacuum to give
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sulfonamide 17 (50.65 kg, 97.5 wt%, 111.7 mol, 98.8 LCAP) in 93.0% yield. H NMR (400 MHz,
DMSO-d6) δ 9.62 (s, 1 H), 8.23 (s, 1 H), 8.12-8.08 (m, 2 H), 7.83 (s, 1 H), 7.45-7.40 (ap. t, J = 8.8
Hz, 2 H), 3.87 (s, 3 H), 3.11 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 163.9 (d, JC-F = 247.9 Hz),
163.3, 161.1, 152.6, 133.2, 132.5 (d, JC-F = 9.5 Hz), 126.6, 125.9, 125.3, 116.9, 116.0 (d, JC-F = 21.9
Hz), 111.5, 108.1, 52.5, 40.6; 19F NMR (376 MHz, DMSO-d6): δ 108.6. HRMS: m/z calcd for
C17H13BrFNO5S: [M+H]+ 441.9755; found 441.9750; mp 213.4 °C.
5-Bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic
acid
(24): Sulfonamide 17 (50.55 kg, 97.5 wt%, 111.4 mol, 1.0 equiv) was dissolved in DMF (231 kg),
and K2CO3 (31 kg, 224 mol, 2.0 equiv) was added. Methyl iodide (20.5 kg, 144.4 mol, 1.3 equiv)
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was added in 1 h while maintaining internal temperature below 30 °C. The mixture was aged at
40 °C for 3 h and cooled to room temperature. The batch was diluted with water (402 kg) and
quenched with HOAc (5.4 kg), The batch was filtered and washed with water (145 kg) to give
crude 23 wet cake (63.2 kg). The wet cake and LiOH monohydrate (13.8 kg, 328.9 mol, 3.0
equiv) were dissolved in THF (776 kg) and water (98 kg).The mixture was heated to reflux and
aged for 6 h. The batch was cooled to 30 °C, diluted with water (180 kg) and quenched with 6 N
aqueous HCl (44 kg) while maintaining internal temperature bewteen 20 and 30 °C. The mixture
was concentrated ~230 L and diluted with 2-MeTHF (480 kg). Additional 6 N HCl (36 kg) was
added to adjust the pH to 3-4. The layers were separated and the organic layer was washed
with 10% aqueous NaCl (194 kg). The layers were separated and the organic layer was
concentrated to ~100 L. n-Heptane (298 kg) was added, and the slurry was aged at 30 °C for 2 h.
The batch was filtered, washed with n-heptane (100 kg), and dried at 50-60 °C under vacuum
for 20 h to give acid 24 (49.0 kg, 97.5 wt%, 108.0 mol, 99.9 LCAP) in 97.0% yield from 17. 1H
NMR (400 MHz, DMSO-d6) δ 13.48 (br s, 1 H), 8.28-8.27 (d, J = 4.2 Hz, 1H), 8.12-8.11 (ap. d, J =
4.2 Hz, 3H), 7.45-7.41 (m, 2H), 3.33 (s, 3H), 3.21 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.3,
163.9 (d, JC-F = 248.6 Hz), 161.3, 152.6, 137.6, 132.6 (d, JC-F = 8.8 Hz), 129.1, 126.1, 125.5, 120.8,
115.9 (d, JC-F = 21.9 Hz), 114.1, 109.2, 38.6, 33.2; 19F NMR (376 MHz, DMSO-d6): δ 108.8; HRMS:
m/z calcd for C16H11BrFNO5S: [M+Na]+ 463.9574; found 465.9546; mp 133.4 °C.
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Methyl
5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-
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1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1 H), 8.20 (s, 1 H), 8.16-8.13 (m, 2H), 7.52-7.48 (t, J = 8.8
5
6
Hz, 2H), 3.96 (s, 3H), 3.28 (s, 3H), 3.27 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.0 (d, JC-F
=
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248.6 Hz), 163.2, 161.8, 152.6, 137.8, 132.5 (d, JC-F = 8.8 Hz), 128.4, 126.0, 125.3, 121.1, 116 (d,
JC-F = 21.9 Hz), 114.2, 108.2, 52.5, 39.3, methansulfonamide carbon overlapped with DMSO-d6;
19F NMR (376 MHz, DMSO-d6) δ 108.4; mp 148.6 °C.
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5-Bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-
carboxamide (19): Acid 24 (49.0 kg, 97.5 wt%, 108.0 mol, 1.0 equiv), HOBt (22.6 kg, 167.2 mol,
1.5 equiv), and EDC-HCl (31 kg, 161.7 mol, 1.5 equiv) were dissolved in DMF (454 kg) at room
temperature. Methylamine HCl salt (22.5 kg, 333.2 mol, 3.1 equiv) was added in portions. NEt3
(51.6 kg, 510.0 mol, 4.7 equiv) was added at 30 °C over 2 h. The mixture was aged at 25-30 °C
for 5 h. Water (497 kg) was added over 4 h while maintaining internal temperature of 25-30 °C.
The mixture was acidified to pH 6-7 by the addition of 4 N aqueous HCl (58 kg). The slurry was
filtered, and the wet cake was washed with water (4x379 kg). The wet cake was dried under
vacuum at 50-60 °C for 24 h. The dry cake was redissolved in DMF (950 kg) at 25-30 °C. Water
(95 kg) was added followed by the addition of seed (45 g). The mixture was aged for 4 h, and
additional water (480 kg) was added over 4 h. The mixture was aged for 4 h. The batch was
filtered, washed with water (360 kg), and dried under vacuum at 50-60 °C for 60 h to give
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benzofuran 19 (44.3 kg, 99.0 wt%, 96.3 mol, 99.8 LCAP) in 89.2% yield. H NMR (400 MHz,
DMSO-d6) δ 8.55 (d, J = 4.8 Hz, 1H), 8.08 (s, 1H), 8.01-7.96 (m, 3H), 7.42 (t, J = 8.8 Hz, 2H), 3.22
(s, 3H), 3.21 (s, 3H), 2.85 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 163.4 (d, JC-F = 247.2 Hz),
162.9, 154.9, 152.3, 137.4, 130.1 (d, JC-F = 8.7 Hz), 129.3, 125.7, 124.6, 120.2, 116.5 (d, JC-F = 21.9
Hz), 113.9, 113.4, 39.4, 26.7 methansulfonamide carbon overlapped with DMSO-d6; 19F NMR
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(376 MHz, DMSO-d6): δ 109.9. HRMS: m/z calcd for C18H16BrFN2O4S: [M+H]+ 455.0071; found
455.0064; mp 247.7 °C.
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6-Chloro-2-iodopyridin-3-ol (9): K2CO3 (28.3 kg, 205 mol, 2.1 equiv) was dissolved in water (116
kg) at 10 °C. Hydroxypyridine 8 (12.9 kg, 99.6 mol, 1.0 equiv) was added followed by the
portion-wise addition of iodine (25.1 kg, 98.9 mol, 0.993 equiv) over 1 h. The mixture was aged
at 10 °C for 2 h and quenched with 10 wt% aqueous Na2S2O3 solution (20.8 kg). The mixture was
aged at 10 °C for 1 h then warmed to 15 °C. The mixture medium was adjusted to pH 6 by the
addition of 6 N aqueous HCl (57.9 kg) and then diluted with MTBE (100.5 kg). The layers were
separated and the aqueous layer was washed with MTBE (100.5 kg). The combined organic
layers were washed successively with water (70 kg) and 25 wt% aqueous NaCl solution (70 kg).
The combined aqueous layers were extracted with MTBE (76.6 kg). The organic layers were
combined and activated characoal 767 (2.2 kg) was added. The mixture was aged at 40 °C for 3
h. The slurry was filtered through celite (12 kg) and washed twice with MTBE (77 kg, 141 kg).
The filtrate was azeotropically dried by MTBE distillation to achieve a water content of 0.8 wt%
and an overall volume of ~70 L. The MTBE was replaced by n-heptane via distillation under
vacuum. The slurry was aged at room temperature for 5 h. The batch was filtered, washed
with n-heptane (19 kg), and dried under vacuum at 40-45 °C for 24 h to give iodopyridine 9
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(22.8 kg, 99.4 wt%, 88.7 mol, 98.6 LCAP) in 89.1% yield. H NMR (400 MHz DMSO-d6) δ 11.15 (s,
1H), 7.31 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz DMSO-d6) δ 107.9,
124.1, 1241.1, 138.3, 154.1. AHR-FAB-MS calcd for C5H3ClINO: [M+H]+ 255.8948; found:
255.9019; mp 189.5 °C.
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Tert-butyl 4-fluoro-1H-indole-1-carboxylate (6): Fluoroindole 4 (17.35 kg, 128.4 mol, 1.0
equiv), DMAP (0.559 kg, 4.58 mol, 3.6 mol%) were dissolved in CH2Cl2 (228 kg) at room
temperature. A solution of Boc2O (29.75 kg, 136.3 mol, 1.06 equiv) in CH2Cl2 (83 kg) was added
over 90 minutes. The mixture was aged at room temperature for 3 h and diluted with water
(38.3 kg). The layers were separated, and the organic layer was washed with water (36.4 kg,
40.2 kg). The CH2Cl2 in the organic layer was replaced by THF via distillation under vacuum to
provide a THF solution of N-Boc indole 6 (80.1 kg, 34.3 wt%, 116.8 mol, 96.3 LCAP) in 91.0%
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yield. H NMR (400 MHz DMSO-d6) δ 7.90 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 3.6 Hz, 1H), 7.37 – 7.30
(m, 1H), 7.07 (dd, J = 10.0, 8.0 Hz, 1H), 6.79 (d, J = 4.0 Hz, 1H), 1.64 (s, 9H); 13C NMR (100 MHz
DMSO-d6) δ 155.5 (d, JC-F = 244.1 Hz), 149.3, 137.2 (d, JC-F = 9.5 Hz), 127.1, 125.7 (d, JC-F = 7.7
Hz), 119.0 (d, JC-F = 22.2 Hz), 111.7, 108.3 (d, JC-F = 18.2 Hz), 102.9, 84.3, 27.6; 19F NMR (376
MHz DMSO-d6) δ 122.0; mp 49.5 °C.
Tert-butyl 4-fluoro-2-(hydroperoxy-λ2-boranyl)-1H-indole-1-carboxylate (7): Diisopropylamine
(31.6 kg, 310.1 mol, 2.7 equiv) was dissolved in THF (173 kg) at -15 °C. To this solution was
added n-BuLi solution (84.2 kg, 2.5 M, 312.3 mol, 2.7 equiv) over 3 h while maintaining internal
temperature between -20 and -5 °C. The solution was aged at -15 °C for 2 h then cooled to -70
°C. The solution of N-Boc indole 6 (79.6 kg, 34.3 wt%, 116.1 mol, 1.0 equiv) was added over 3 h
while maintaining the internal temperature between -75 and -65 °C. The transfer lines were
rinsed with THF (10 kg) and the mixture was aged at -70 °C for 1 h. Triisopropyl borate (33.8 kg,
179.7 mol, 1.5 equiv) was added over 2 h while maintaining the internal temperature between -
75 and -65 °C. The mixture was aged at -70 °C for 2 h. The mixture was quenched with a
solution of acetic acid (51 kg) in THF (51 kg) while maintaining the internal temperature less
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than -10 °C. The pH of the quenched mixture was 4. The temperature was adjusted to -15 °C
and diluted with water (54 kg). The batch was then aged at 15 °C for 1 h. The layers were
separated and the organic layer was washed twice with 10 wt% aqueous NaCl solution (119 kg,
157 kg) to give a solution of boronic acid 7 (386.6 kg, 8.4 wt%, 116.4 mol, 95.7 LCAP) in 100%
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assay yield. H NMR (400 MHz DMSO-d6) δ 8.30 (s, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.29 (m, 1H),
7.03 (dd, J = 9.6, 8.0 Hz, 1H), 6.68 (s, 1H), 1.61 (s, 9H); 13C NMR (100 MHz DMSO-d6) δ 154.8 (d,
JC-F = 243.5 Hz), 149.6, 138.4 (d, JC-F = 10.2 Hz), 139.2 (br s), 124.9, 118.9 (d, JC-F = 21.9 Hz),
111.0, 107.6 (d, JC-F = 18.2 Hz), 106.6, 84.6, 27.5; 19F NMR (376 MHz DMSO-d6) δ 112.7; mp 79.0
°C.
6-Chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (10): The solution of boronic acid 7 (313.2 kg,
8.4 wt%, 94.3 mol, 1.15 equiv) was combined with iodide 9 (21 kg, 99.4 wt%, 81.7 mol, 1.0
equiv) and diluted with water (120 kg). The mixture was degassed by subsurface argon bubbling
for 2 h. KHCO3 (25 kg, 250 mol, 3.1 equiv), PPh3 (2.2 kg, 8.39 mol, 10 mol%), and Pd(OAc)2 (0.97
kg, 96 wt%, 4.15 mol, 5.1 mol%) were added. The mixture was degassed again by subsurface
argon bubbling for 2 h. The mixture was aged at 65 °C for 24 h. The THF in the solution replaced
by MTBE via vacuum distillation until residual THF was 3.3 wt%. The mixture was filtered
through celite (12 kg) and the residue was washed with MTBE (2x78 kg). The layers in the
combined filtrate were separated and the organic layer was washed with water (103 kg). The
MTBE solution was dried by azeotropic distillation with additional MTBE to prepare a crude
solution of indole 10 (~400 L). The water content of this solution was 0.8 wt%. Ecosorb C-941
(4.8 kg) was charged to this solution and the slurry was aged at 40 °C for 3 h. The slurry was
filtered and washed four times with MTBE (101 kg, 80 kg, 120 kg, 120 kg). The MTBE in the
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solution was replaced by CH2Cl2 via vacuum distillation to achieve a slurry of product in ~50 L of
CH2Cl2 containing 1.4 wt% MTBE. The slurry was aged at room temperature for 5 h. The batch
was filtered and washed with CH2Cl2 (41 kg), dried under vaccuum at room temperature for 24
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h to give indole 10 (17.1 kg, 97.7 wt%, 63.6 mol, 99.2 LCAP) in 77.8% yield. H NMR (400 MHz
DMSO-d6) δ 11.63 (s, 1H), 11.10 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.34 (s,
1H), 7.29 (d, J = 8.8 Hz, 1H), 7.10 (m, 1H), 6.78 (m, 1H); 13C NMR (100 MHz DMSO-d6) δ 155.9 (d,
JC-F = 243.4 Hz), 150.7, 139.0 (d, JC-F = 10.9 Hz), 138.8, 137.2, 133.8, 127.1, 123.1, 122.9 (d, JC-F
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(376 MHz DMSO-d6) δ 122.5; AHR-FAB-MS m/z calcd for C13H8ClFN2O: [M+H]+ 263.0309; found
263.0385; mp 233.0°C.
2-Chloro-11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indole (2): Two batches of
hydropyridine 10 (17.05 kg at 97.7 wt% and 1.1 kg at 99.5 wt%, 67.6 mol total, 1.0 equiv) and
Cs2CO3 (45.0 kg, 138 mol, 2.0 equiv) were heated in N,N-dimethylacetamide (DMAc, 139 kg) at
110-115 °C. A solution of ICH2Cl (14.8 kg, 83.9 mol, 1.2 equiv) in DMAc (34 kg) was added over 3
h. The transfer lines were rinsed with DMAc (9 kg). The mixture was aged at 110-115 °C for 15
h. The batch was cooled to room temperature, filtered through celite (10 kg), and washed twice
with DMAc (2x33 kg). Water (143 kg) was added to the filtrate over 4 h while maintaining the
internal temperature between 15 and 25 °C. The batch was aged at 20 °C for 1 h. The batch was
filtered and washed successively with a mixture of DMAc and water (36 kg, 2:1 v/v) and water
(36 kg) to give a wet cake of chloroindolopyridine 2 (24.5 kg, 67.3 wt%, 60.0 mol) in 88.8%
yield.
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