Development of Flexible and Scalable Routes to Two Phosphatidinylinositol-3-kinase Delta Inhibitors via a Common Intermediate Approach

Article abstract of DOI:10.1021/acs.oprd.8b00006

This paper describes the discovery and development of a flexible route to two candidate drug molecules by a common intermediate approach. Key reactions include Negishi and Suzuki couplings to form biaryl bonds. Conditions for a Miyaura borylation of heteroaryl bromides were also developed. Heteroaryl trifluoroborates and aryl chlorides were used as coupling partners in the Suzuki reaction, thereby minimizing detrimental side reactions such as protodeboronation and oxidative homocoupling. A complementary set of reaction conditions using pinacolboronates with potassium bifluoride as an additive were also developed and used to make 5 kg of drug substance for use in early-phase clinical trials.

Full text of DOI:10.1021/acs.oprd.8b00006

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Development of Flexible and Scalable Routes to Two
Phosphatidinylinositol-3-kinase Delta Inhibitors via a Common
Intermediate Approach
Dean Edney, David G. Hulcoop, John H. Leahy, Lois E. Vernon,† Mark D. Wipperman,†
Robert N. Bream,*,† and Michael R. Webb*
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
ABSTRACT: This paper describes the discovery and development of a flexible route to two candidate drug molecules by a
common intermediate approach. Key reactions include Negishi and Suzuki couplings to form biaryl bonds. Conditions for a
Miyaura borylation of heteroaryl bromides were also developed. Heteroaryl trifluoroborates and aryl chlorides were used as
coupling partners in the Suzuki reaction, thereby minimizing detrimental side reactions such as protodeboronation and oxidative
homocoupling. A complementary set of reaction conditions using pinacolboronates with potassium bifluoride as an additive were
also developed and used to make 5 kg of drug substance for use in early-phase clinical trials.
lass I phosphatidinylinositol-3-kinases (PI-3-kinases) are a
family of enzymes responsible for the production of
electon-rich phosphine ligands.8 The medicinal chemistry route
had made the oxazole−indazole bond using a Stille coupling
between chlorooxazole 5 and indazole stannane 6, available
from the protected iodoindazole 7 (Scheme 1).7 Studies
showed that the benzenesulfonyl group could be selectively
introduced on N1, was reasonably robust and inert throughout
the synthetic sequence, and could then be readily cleaved to
reveal the naked indazole. However, it was found that
chlorooxazole 5 was susceptible to decomposition at moderate
temperatures, and scaling up organotin chemistry with volatile
byproducts to multikilogram scale was unattractive.
Alternative protocols such as Suzuki and Negishi reactions
were therefore investigated. Suzuki reactions gave low yields
and still required use of the unstable chlorooxazole. A Negishi
reaction allowed employment of the parent oxazole ester 9:
deprotonation at C2 followed by transmetalation provided
straightforward access to the organozinc species 10, which
coupled efficiently and selectively with iodoindazole 7 upon
addition of tetrakis(triphenylphosphine)palladium (Scheme
2).9
With a reliable protocol for construction of the first biaryl
bond, routes to the oxazole ester were next examined. The ethyl
ester 9 was commercially available but not in sufficient
quantities to fund a multikilogram plant campaign. A range of
solvents and inorganic bases were examined for the reaction
between toluenesulfonylmethyl isocyanate (Tosmic, 11) and
ethyl glyoxylate (12).10 Screening ethereal and alcoholic
solvents showed that tetrahydrofuran (THF) with an alcoholic
cosolvent gave the best conversion, and cesium carbonate was
the optimum base. The product oxazole was found to be
unstable under the elevated temperatures required for reaction,
and thus, processing conditions giving a fast reaction were
sought. Methanol gave a much faster reaction than ethanol and
was thus selected, despite the fact that partial transesterification
was observed. The mixed esters 9 and 13 performed well in the
C
phosphatidinylinositol-3,4,5-trisphosphate, a cell-membrane-
bound phospholipid and important secondary messenger in a
range of physiological processes, including cell growth,
proliferation, differentiation, and inflammatory response.1,2
The delta isoform is located primarily in leucocytes, and
inhibitors may have therapeutic potential as anti-inflammatories
and in autoimmune disease.3,4 The same pathway has been
implicated in potentiating the inflammatory response to
allergens in the airways.5 Dosing of selective PI-3-kinase δ
inhibitors to the nose has been shown to reduce lung
inflammation and airway hyper-responsiveness in asthma
models and to reduce release of mast cells in nasal tissue,
and thus, these inhibitors show potential as nonsteroidal anti-
inflammatories for the treatment of steroid-insensitive
asthmas.6 Topical administration via a dry-powder inhaler
would reduce systemic side effects.
Compounds 1 and 2 were under development as selective
inhaled PI-3-kinase δ inhibitors (Figure 1).7 Synthetic routes to
both that could produce multikilogram amounts of drug to
fund early-phase clinical trials and safety assessment studies
were required. The compounds share an indazole−oxazole core
but are differentiated by the oxazole-linked polar amine
headgroups and indazole-linked heterocyclic tail groups.
Given the high chances of attrition during development, the
development of a route via a late-stage common intermediate
was particularly attractive since it would allow material to be
stockpiled and converted to whichever candidate would be
required while reducing the risk of wasted synthetic endeavors.
Retrosynthetic analysis revealed bromide 3 as a suitable
common intermediate.
Synthetic investigations began with 6-chloro-4-iodoindazole
(4), which was purchased from a contract research organ-
ization. Introduction of orthogonal halides at the 4- and 6-
positions would allow construction of the two biaryl bonds in
selective and sequential fashion, as oxidative insertion into the
C−Cl bond requires a more active catalyst system featuring
Received: January 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00006
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Figure 1. Two drug candidates originate from a common synthetic intermediate.
Scheme 1. Construction of the Indazole−Oxazole Biaryl Linkage by Stille Reaction
Scheme 2. Construction of the Indazole−Oxazole Biaryl Linkage by Negishi Reaction
Scheme 3. Telescoped Route to Bromide 3
Scheme 4. Conversion of Bromide 3 to Amines 19 and 20
B
DOI: 10.1021/acs.oprd.8b00006
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Scheme 5. Synthesis of Pyridineboronate 21
Scheme 6. Synthesis of Trifluoroborate 27 and Subsequent Suzuki Reaction
subsequent Negishi coupling, again affording a mixture of
products 14 and 15. Addition of diisobutylaluminum hydride to
the completed Negishi reaction mixture then reduced both
esters to afford a single alcohol product, 16, which was isolated
as a solid. Conversion to alkyl bromide 3, the required common
intermediate, was accomplished with triphenylphosphine
dibromide (Scheme 3).
system was not particularly robust, however, with larger-scale
reactions sometimes stalling after precipitation of palladium
black. It seemed likely that formation of palladium black would
be accelerated by high local concentrations of unligated
palladium(0) and that addition of excess ligand should prevent
this. However, increasing the Pd:ligand ratio from 1:2 to 1:4 led
to much slower reactions. This problem was eventually solved
simply by halving the loadings of palladium (from 2 to 1 mol
%) and ligand (from 10 to 5 mol %) and diluting from 10 to 20
volumes of dioxane, thus reducing the Pd(0) concentration 4-
fold. It is also known that dibenzylideneacetone (DBA) is not
an innocent ligand and that tuning its electronics can have an
effect on the rate and outcome of palladium-catalyzed
processes.13 Closer analysis of LC−MS spectra recorded during
reactions revealed the presence of Michael addition products
from tricyclohexylphosphine and DBA. Removal of tricyclohex-
ylphosphine from the reaction system would also lead to
unligated palladium(0) and precipitation of palladium black. It
was subsequently found that simply adding additional Pd2dba3
to a stalled reaction restarted the catalytic cycle and allowed
complete consumption of the starting material, albeit with
increased protodeboronation due to extended processing times.
The Suzuki reaction between boronate 21 and aryl chloride
19 was next investigated. A screen of catalysts, bases, and
solvents revealed that a combination of 5 mol % catalyst 25
(see Scheme 6) and sodium bicarbonate in aqueous 2-propanol
gave rapid and complete consumption of aryl chloride 19. This
solvent mixture allowed isolation of the product 26 in excellent
yield and purity. However, significant protodeboronation and
homodimerization of boronate 21 were observed, and 2 equiv
was required to fully consume all of the aryl chloride.14 Work
by the groups of Molander15 and Lloyd-Jones16 indicates that
the use of trifluoroborates in Suzuki reactions reduces these
detrimental processes. Thus, we set about attempting to make
trifluoroborate 27 from pinacolboronate 21.17 Treatment of
boronate ester 21 with potassium bifluoride in aqueous
methanol, dioxane, THF, or acetone resulted in trifluoroborate
At this point, the routes to the two drug substances diverge.
Substitution of bromide 3 with the two amines 17 and 18 was
next investigated and was achieved in both cases by adding
triethylamine to a mixture of the two coupling partners in
acetone. Less than 5% quaternization was observed, and the
products 19 and 20 were subsequently crystallized by addition
of water (Scheme 4). It was later found that the purity of these
products was key to a successful Suzuki reaction. Thus, for the
reaction of 3 with piperazine 18, the reaction solvent was
switched to dimethyl sulfoxide (DMSO), which significantly
improved the isolated purity. An optional recrystallization of
both products from DMSO was also introduced, dependent on
the outcome of user tests in the downstream chemistry.
With the pair of indazole chlorides in hand, preparation of
the required heteroaryl pinacolboronate coupling partners was
next investigated. Pyridineboronate 21 was synthesized in four
steps from 5-bromo-2-chloro-3-nitropyridine (22) (Scheme 5).
Treatment with sodium methoxide in methanol followed by
reduction of the nitro group afforded aminopyridine 23 as its
hydrochloride salt in 90% yield. Mesylation then afforded 24,
also in excellent yield. Finally, Miyaura borylation afforded
pinacolboronate 21. The latter reaction was first carried out
under standard conditions using PdCl2(dppf) as the catalyst in
N,N-dimethylformamide (DMF).11 However, the reaction took
upward of 8 h at 100 °C to complete, and 30%
protodeboronation was observed under these conditions. The
combination of tricyclohexylphosphine and tris-
(benzylideneacetone)dipalladium in dioxane proved to be a
much more reactive catalyst system, with the reaction taking
less than half an hour to complete and the yield of
protodeboronated material being reduced to 5%.12 This latter
1
formation, observable by H NMR spectroscopy. However, an
C
DOI: 10.1021/acs.oprd.8b00006
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Scheme 7. Optimization of Conditions for the Suzuki Reaction with Indole Pinacolboronate 29
Scheme 8. Deprotection To Afford the Two Drug Substances
equilibrium between pinacolboronate and trifluoroborate exists,
and 4 equiv of KHF2 was required to ensure complete
trifluoroborate formation. Under these conditions, crystalliza-
tion and thus isolation of the trifluoroborate salt was inhibited.
Methods to push the equilibrium toward trifluoroborate
without using such an excess of fluoride, such as multiple
evaporations to dryness to remove pinacol18a or addition of
sodium periodate to oxidatively cleave pinacol,18b were not
considered practical on a manufacturing scale.18c The
trifluoroborate salt was eventually isolated by reducing the
water content in aqueous dioxane to 5%, thus allowing an
inorganic-rich aqueous layer to separate and be decanted.
Azeotropic drying of the resultant solution afforded trifluor-
oborate 27, albeit containing 30 wt % inorganic salts, in 90%
yield after correction for purity (Scheme 6). This step was
readily telescoped with the prior borylation reaction, since they
share the same solvent, to deliver a one-pot borylation/
fluorination process.
Coupling of trifluoroborate 27 and aryl chloride 19 was next
attempted. After screening of a series of electron-rich ligands19
and bases, a combination of palladium acetate and tricyclohex-
ylphosphine with potassium phosphate as the base in aqueous
2-propanol was selected. Under these conditions, protodeboro-
nation and homodimerization were suppressed, and 1.1 equiv
of trifluoroborate was sufficient to consume all of chloride 19.
In contrast, the formation of indoletrifluoroborate 28 for the
synthesis of 1 proved to be much more difficult. The use of 6
equiv of KHF2 and heating to 60 °C were required to force
complete trifluoroborate formation from indole pinacolboro-
nate 29, but attempts to isolate the salt in analogous fashion to
pyridyltrifluoroborate 27 met with failure. Trifluoroborate salt
28 also proved to be susceptible to decomposition, especially at
elevated temperature. In Suzuki reactions, potassium trifluor-
oborates act as sources of the corresponding boronic acids,
which are the primary species involved in transmetalation to
palladium and subsequent reductive elimination.16a For
successful implementation of this strategy, however, the
hydrolysis to form the boronic acid must happen more slowly
or at a rate equivalent to the rate of consumption of the boronic
acid via the desired catalytic cycle to prevent its accumulation
and participation in detrimental side reactions.20 We reasoned
that adding sufficient potassium bifluoride to a Suzuki reaction
of pinacolboronate 29 should have a similar effect and would
thus allow clean coupling without significant protodeborona-
tion and homodimerization.21 We were delighted to find that
simply adding 2 equiv of KHF2 to the reaction mixture did
indeed allow complete consumption of aryl chloride 20 with
only 1.1 equiv of added pinacolboronate 29, affording product
30 in 82% yield (Scheme 7). The same conditions also allow
coupling of pyridineboronate 21 and aryl chloride 19 in 99%
yield (Scheme 6). The effectiveness of potassium and cesium
fluoride as bases in Suzuki reactions has also been
demonstrated, and they would be preferred as fluoride sources
from a process chemistry point of view because of their lower
D
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toxicity and reduced glass etching, a significant issue with the
use of KHF2.22,23 However, replacement of KHF2 with KF
under otherwise unaltered reaction conditions led to 20%
protodeboronation and incomplete consumption of aryl
chloride 20. While pinacolboronate 29 is commercially available
on a small scale, the conditions developed for the synthesis of
pyridylboronate 21 also proved to be successful for its
preparation starting from 4-bromoindole (31). Despite a
predilection for polar aprotic solvents in the literature,
toluene24 proved to be a much more effective solvent than
dioxane, reducing both the reaction time and the propensity for
palladium black precipitation and reaction stalling.
With effective Suzuki coupling methods established, all that
remained was to remove the protecting groups and isolate the
two drug substances. Indole 30 is sparingly soluble in aqueous
media, and thus, elevated temperature and a phase transfer
catalyst were required to cleave the sulfonate group. In contrast,
the sulfonamide group in 26 is acidic enough to be
deprotonated by sodium hydroxide, which allows solubility
and deprotection in water at ambient temperature (Scheme 8).
In summary, synthetic routes to two investigational PI-3-
kinase δ inhibitors have been developed. The indazole−oxazole
core, common to the two compounds, allowed us to access
both through a late-stage common intermediate. Conditions for
the Miyaura borylation of heteroaryl bromides were developed,
and in one case a one-pot conversion to the corresponding
potassium trifluoroborate salt was demonstrated. The use of
potassium trifluoroborate salts was demonstrated to reduce
detrimental side reactions such as protodeboronation and
homodimerization in Suzuki coupling reactions. A comple-
mentary approach was also demonstrated whereby addition of
potassium bifluoride to Suzuki couplings of pinacolboronate
esters similarly prevented these side reactions. These optimized
conditions allow the amount of the boronate ester required to
consume all of the aryl chloride partner to be reduced from 2 to
1.1 equiv. The application of such conditions should find
application in Suzuki processes in instances where access to the
potassium trifluoroborate salts is not possible.
was added over 1 h. The slurry was filtered, and the solid was
washed with heptane/toluene (4:1, 40 mL) and heptanes (40
mL) and then dried in vacuo at 55 °C to afford 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (29) (15.1 g,
62.1 mmol, 61%) as a tan solid. δH (CDCl3, 400 MHz) 1.42
(12H, s), 7.07−7.10 (1H, m), 7.22 (1H, dd, J = 8.1, 7.1 Hz),
7.25−7.27 (1H, m), 7.50 (1H, dt, J = 8.1, 1.0 Hz), 7.67 (1H,
dd, J = 7.1, 0.7 Hz), 8.19 (1H, br, s); δC (CDCl3, 100 MHz)
25.0, 83.4, 104.6, 113.9, 121.3, 124.5, 127.9, 132.5, 135.1 (no
signal for C−B carbon); HRMS m/z calcd for C14H19BNO2
244.1503, found 244.1503; mp 172−174 °C.
6-Chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole (7). A
mixture of 6-chloro-4-iodoindazole (4) (17.1 kg, 61.4 mol),
sodium hydroxide (5.54 kg, 138 mol), and tetrabutylammo-
nium hydrogen sulfate (1.04 kg, 3.07 mol) was stirred in THF
(171 L) at 20 °C for 1 h. The reaction mixture was cooled to 15
°C, and benzenesulfonyl chloride (12.5 kg, 70.8 mol) was
added over 30 min, with the reaction temperature maintained
at <25 °C. The resulting reaction mixture was stirred at 20 °C
for 1 h and then added to hydrochloric acid solution (0.25 M,
350 L) at 0 °C with vigorous stirring, resulting in precipitation
of an orange solid. The mixture was aged for 1 h and filtered,
and the solid was washed with water (2 × 51 L) and dried in
vacuo at 40 °C to afford 6-chloro-4-iodo-1-(phenylsulfonyl)-
1H-indazole (7) (25.2 kg, 60.2 mol, 99%) as an orange solid. δH
((CD3)2SO, 400 MHz) 7.65 (2H, app. t, J = 7.6 Hz), 7.78 (1H,
tt, J = 7.6, 1.0 Hz), 7.91 (1H, d, J = 1.5 Hz), 8.02 (2H, dd, J =
7.6, 1.0 Hz), 8.16−8.18 (1H, m), 8.41 (1H, d, J = 0.7 Hz); δC
((CD3)2SO, 100 MHz) 89.0, 112.0, 127.3, 128.8, 130.0, 133.4,
135.1, 135.4, 136.0, 139.2, 144.1; HRMS m/z calcd for
C13H9ClIN2O2S 418.9113, found 418.9106; mp 178−182 °C.
(2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-
oxazol-5-yl)methanol (16). To a suspension of cesium
carbonate (47.0 kg, 144 mol) in THF (200 L) were added
methanol (16.4 kg, 512 mol) and ethyl glyoxylate (12) (50 wt
% in PhMe, 57.8 kg, 283 mol), and the suspension was heated
to 50 °C for at least 30 min. To the suspension was then added
p-toluenesulfonylmethyl isocyanide (11) (25.0 kg, 128 mol),
and the suspension was heated to 60 °C for 1 h. The mixture
was cooled to 20 °C, and acetic acid (38.5 kg, 641 mol) was
added, after which the suspension stirred at 20 °C for 30 min.
To the suspension was then added a solution of potassium
hydrogen carbonate (57.7 kg, 576 mol) in water (200 L),
followed by extraction with diisopropyl ether (4 × 100 L). The
combined organic layers were washed with brine (25 L) and
distilled down to a volume of 50 L (200 mbar, 35 °C).
Diisopropyl ether (125 L) was charged, and then the mixture
was distilled down to a volume of 50 L (200 mbar, 35 °C).
CAUTION: to avoid peroxide formation, diisopropyl ether
distillate should be treated with a stabilizer. The solution was
diluted with THF (110 L) and added to a suspension of zinc
chloride (25.7 kg, 189 mol) in THF (110 L) at −10 °C. A
solution of lithium hexamethyldisilazide (1.0 M in THF, 94.6 L,
94.6 mol) was added over 45 min, and the solution was aged at
−10 °C for 1 h. Then 7 (22.0 kg, 52.6 mol) and
tetrakis(triphenylphosphine)palladium (1.80 kg, 1.56 mol)
were added, and the mixture was heated to 60 °C for 15 h.
The solution was cooled to 0 °C, and diisobutylaluminum
hydride (25 wt % in PhMe, 109.8 kg, 193 mol) was added over
1 h. The solution was aged at 0 °C for a further 1 h and then
quenched by addition to a solution of citric acid (44 kg, 229
mol) in water (176 L) over 1 h, with the temperature of the
contents maintained at <10 °C. The reaction mixture was
EXPERIMENTAL SECTION
General Methods. All commercially available chemicals
■
and solvents were used as received without any further
1
purification. H and 13C NMR spectra were acquired on a
Bruker spectrometer at frequencies of 400 and 100 MHz,
respectively. High-resolution mass spectra were recorded on a
linear ion trap combined with a Fourier transform ion cyclotron
resonance mass spectrometer using an electrospray ionization
source operated in positive ion mode. Observed m/z values and
empirical formulas provided refer to [M + H]+. Melting points
were recorded using an automated melting point apparatus.
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
indole (29). Tris(benzylideneacetone)dipalladium (467 mg,
0.510 mmol) and tricyclohexylphosphine (572 mg, 2.04 mmol)
were combined in degassed toluene (20 mL) and aged for 30
min. The resultant purple solution was added via cannula to a
suspension of 4-bromoindole (31) (20.0 g, 102 mmol),
bis(pinacolato)diboron (31.1 g, 122 mmol), and potassium
acetate (20.0 g, 204 mmol) in degassed toluene (100 mL) at
100 °C. After 4 h, the mixture was cooled to 60 °C and filtered;
the solid was washed with toluene (2 × 40 mL), and the filtrate
volume was reduced under vacuum (100 mbar, 50−60 °C) to
80 mL. The mixture was aged at 60 °C for 1 h, then cooled to
20 °C over 2 h, and aged for 1 h, and then heptane (240 mL)
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warmed to 20 °C and extracted with EtOAc (198 L). The
resultant mixture was stirred at 20 °C for 1 h and filtered, and
the organic phase was separated and washed with water (2 × 66
L). The organic layer was distilled at reduced pressure (30
mbar, 40 °C), then diluted with DMSO (242 L), and further
distilled at reduced pressure (30 mbar, 40 °C) to remove all
low-boiling solvent. The solution was cooled to 20 °C, and
water (110 L) was added over 30 min. The resultant
suspension was then stirred at 20 °C for 14 h and filtered,
and the solid was washed with 1:1 DMSO/water (66 L) (3
vols) followed by water (2 × 66 L) and dried in vacuo at 60 °C
to afford (2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-
oxazol-5-yl)methanol (16) (17.4 kg, 44.6 mol, 85%) as a tan
solid. δH (CDCl3, 400 MHz) 4.60 (2H, d, J = 5.9 Hz), 5.55
(1H, t, J = 5.9 Hz), 7.35 (1H, s), 7.64 (2H, app. t, J = 7.6 Hz),
7.76 (1H, dd, J = 7.6, 1.2 Hz), 7.92 (1H, d, J = 1.7 Hz), 8.04
(2H, dd, J = 7.6, 1.2 Hz), 8.26 (1H, dd, J = 1.7, 0.7 Hz), 8.99
(1H, d, J = 0.7 Hz); δC (CDCl3, 100 MHz) 53.5, 113.7, 120.6,
121.5, 122.4, 125.9, 127.4, 130.0, 134.9, 135.4, 136.0, 140.7,
141.4, 154.0, 157.1; HRMS m/z calcd for C17H13ClN3O4S
390.0310, found 390.0311; mp 170−172 °C.
5-(Bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-
indazol-4-yl)oxazole (3). A mixture of 16 (24.25 kg, 62.2
mol) and triphenylphosphine dibromide (25.5 kg, 60.4 mol)
was stirred in DCM (360 L) at 20 °C for 1 h. To the reaction
mixture were then added MeOH (19.5 L) and 8% w/w sodium
hydrogen carbonate solution (8 wt %, 243 L) over 15 min. The
organic phase was separated, and the aqueous layer was re-
extracted with DCM (120 L); the combined organics were
washed with water (120 L) and distilled down to 120 L. MeOH
(360 L) was added, and the mixture was distilled down to 360
L (260 mbar, 20 °C). The resultant suspension was aged at 20
°C for 9 h and then filtered, washed with MeOH (2 × 25 L),
and dried in vacuo at 30 °C to afford 5-(bromomethyl)-2-(6-
chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole (3) (20.9
kg, 46.1 mol, 74%) as a tan solid. δH (CDCl3, 400 MHz)
4.95 (2H, s), 7.56 (1H, s), 7.63 (2H, app. t, J = 7.6 Hz), 7.76
(1H, dd, J = 7.6, 1.2 Hz), 7.91 (1H, d, J = 1.7 Hz), 8.04 (2H,
dd, J = 7.6, 1.2 Hz), 8.28 (1H, dd, J = 1.7, 0.7 Hz), 8.93 (1H, d,
J = 0.7 Hz); δC (CDCl3, 100 MHz) 21.2, 114.3, 120.7, 121.0,
122.8, 127.4, 128.3, 130.1, 135.0, 135.5, 136.0, 140.7, 141.3,
149.8, 158.1; HRMS m/z calcd for C17H12BrClN3O3S
451.9466, found 451.9463; mp 156−158 °C.
2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-
isopropylpiperazin-1-yl)methyl)oxazole (20). To a sol-
ution of N-isopropylpiperazine (18) (3.5 kg, 27.3 mol) in
DMSO (80 L) was added 3 (10.4 kg, 23.0 mol) in four portions
over 1 h, and the mixture was aged for a further hour. The
mixture was then heated to 50 °C and aged for 1 h, and
triethylamine (2.20 kg, 21.7 mol) added over 10 min. The
mixture was aged for 40 min, cooled to 20 °C over 1 h, and
further aged for 2 h. The resultant slurry was filtered, and the
solid was washed with DMSO (31 L) followed by 1:2 acetone/
water (3 × 21 L) and dried at 60 °C in vacuo to afford 2-(6-
chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpi-
perazin-1-yl)methyl)oxazole 20 (8.15 kg, 16.3 mol, 71%).
Example of recrystallization: 20 (14.7 kg, 29.4 mol) was
dissolved in DMSO (118 L) at 75 °C, and the solution was
clarified, cooled to 20 °C over 2 h, aged for 10 h, and filtered.
The solid was washed with DMSO (30 L) and then 1:3
acetone/water (59 L then 29 L) and dried in vacuo at 60 °C to
afford purified 20 (12.8 kg, 28.3 mol, 87%) as an off-white solid.
δH ((CD3)2SO, 400 MHz) 0.91 (6H, d, J = 6.6 Hz), 2.32−2.48
(8H, m), 2.56 (1H, sept., J = 6.6 Hz), 3.68 (2H, s), 7.34 (1H,
s), 7.60−7.66 (2H, m), 7.76 (1H, tt, J = 7.5, 1.2 Hz), 7.87 (1H,
d, J = 1.7 Hz), 8.01−8.05 (2H, m), 8.23−8.25 (1H, m), 8.92
(1H, d, J = 0.7 Hz); δC ((CD3)2SO, 100 MHz) 18.2, 47.8, 51.3,
52.5, 53.5, 113.7, 120.6, 121.5, 122.4, 127.4, 127.7, 130.1, 134.9,
135.4, 136.0, 140.7, 141.4, 150.8, 157.3; HRMS m/z calcd for
C24H27ClN5O3S 500.1518, found 500.1513; mp 121−126 °C.
2-(6-(1H-Indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-
yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (30). A
solution of palladium acetate (58.1 g, 259 mmol) and
tricyclohexylphosphine (143 g, 510 mmol) in degassed 2-
propanol (32 L) was added to a degassed mixture of 20 (6.40
kg, 12.8 mol), 29 (3.42 kg, 14.1 mol), potassium phosphate
(3.26 kg, 15.4 mol), and potassium bifluoride (2.20 kg, 28.2
mol) in 2-propanol (32 L) and water (32 L) at 80 °C. The
mixture was aged at 80 °C for 17 h, cooled to 20 °C, aged for a
further 1 h, and filtered. The solid was washed sequentially with
1:1 isopropyl alcohol (IPA)/water (2 × 12 L) and water (2 ×
13 L) and dried in vacuo at 60 °C to afford 2-(6-(1H-indol-4-
yl)-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpipera-
zin-1-yl)methyl)oxazole (30) (6.12 kg, 10.5 mol, 82%) as a tan
solid. δH ((CD3)2SO, 400 MHz) 0.89 (6H, d, J = 6.6 Hz),
2.28−2.48 (8H, m), 2.52 (1H, sept, J = 6.6 Hz), 3.69 (2H, s),
6.59−6.63 (1H, m), 7.25−7.35 (3H, m), 7.51−7.57 (2H, m),
7.63 (2H, app. t, J = 7.6 Hz), 7.74 (1H, t, J = 7.6 Hz), 8.00 (2H,
d, J = 7.6 Hz), 8.25 (1H, d, J = 1.2 Hz), 8.50 (1H, s), 8.99 (1H,
d, J = 0.7 Hz) 11.45 (1H, br s); δC ((CD3)2SO, 100 MHz) 18.1,
47.8, 51.3, 52.5, 53.5, 99.5, 112.2, 112.9, 119.4, 120.5, 120.7,
121.5, 122.9, 125.5, 126.8, 127.2, 127.5, 130.0, 131.0, 135.2,
136.3, 136.5, 141.1, 141.6, 142.9, 150.2, 158.5; HRMS m/z
calcd for C32H33N6O3S 581.2329, found 581.2316; mp 242−
245 °C.
2-(6-(1H-Indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropyl-
piperazin-1-yl)methyl)oxazole (1). Potassium hydroxide
(5.78 kg, 103 mol) was added to a suspension of 30 (12.0
kg, 20.6 mol) and cetyltrimethylammonium bromide (370 g,
1.02 mol) in 2-methyltetrahydrofuran (120 L), and the mixture
was heated to 80 °C for 4 h, cooled to 60 °C, and washed with
water (2 × 120 L). 2-Methyltetrahydrofuran (60 L) was added,
and the solution was filtered and distilled down to 24 L (150
mbar, 30 °C), followed by two cycles of dilution with 3-
pentanone (36 L) and distillation down to 36 L (100 mbar, 30
°C). The resultant slurry was aged for 2 h and then filtered, and
the solid was washed with 3-pentanone (12 L) and dried in
vacuo at 60 °C to afford 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-
5-((4-isopropylpiperazin-1-yl)methyl)oxazole (1) (7.78 kg,
17.7 mol, 86%) as an off-white solid. δH ((CD3)2SO, 400
MHz) 0.92 (6H, d, J = 6.6 Hz), 2.38−2.50 (8H, m), 2.57 (1H,
sept, J = 6.6 Hz), 3.72 (2H, s), 6.58−6.63 (1H, m), 7.21−7.27
(2H, m), 7.31 (1H, s), 7.45−7.51 (2H, m), 7.90 (1H, s), 8.08
(1H, d, J = 1.2 Hz), 8.59 (1H, d, J = 0.7 Hz), 11.34 (1H, br, s),
13.42 (1H, br, s); δC ((CD3)2SO, 100 MHz) 18.2, 47.9, 51.4,
52.5, 53.5, 99.9, 111.3, 113.0, 118.0, 119.0, 119.1, 119.9, 121.5,
125.7, 126.2, 127.2, 132.3, 133.6, 136.4, 139.0, 141.2, 149.4,
160.0; HRMS m/z calcd for C26H29N6O 441.2397, found
441.2392; mp 154−157 °C.
5-Bromo-2-methoxypyridin-3-ammonium Chloride
(23). To a suspension of 5-bromo-2-chloro-3-nitropyridine
(22) (20.0 kg, 84.2 mol) in methanol (80 L) was added a
solution of sodium methoxide in methanol (25 wt %, 23.6 kg,
109 mol) over 1 h, and the mixture was aged for a further 30
min. Water (100 L) was added over 30 min, with the
temperature maintained at <25 °C. The mixture was
F
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Article
concentrated to 120 L by distillation (100 mbar, 30 °C), and
the resulting slurry was filtered, washed with water (2 × 50 L),
and dried in vacuo at 35 °C. The resultant solid was taken up in
industrial methylated spirit (IMS) (225 L), and iron powder
(325 mesh, 16.0 kg, 286 mol) and water (8.7 L) were added,
after which the mixture was heated to 40 °C. A solution of HCl
(9%, 13.6 kg, 33.5 mol) was added over 2.5 h, and the mixture
was aged at 40 °C for a further 4 h. The mixture was cooled to
20 °C and filtered through Celite, and the vessel and cake were
washed with IMS (76 L). The combined filtrates were distilled
(100 mbar, 30 °C) to 94 L, and toluene (187 L) was added.
The mixture was distilled (100 mbar, 30 °C) to 93 L, and
toluene (93 L) was added. The solution was cooled to 20 °C,
and HCl in IPA (5 M, 17.7 L, 88.5 mol) was added over 30
min. The slurry was aged for 1 h and filtered, and the cake was
washed with toluene (77 L) and dried under vacuum at 40 °C
to afford 5-bromo-2-methoxypyridin-3-ammonium chloride
(23) (18.1 kg, 75.6 mol, 90%) as a gray solid. δH (CDCl3,
400 MHz) 3.87 (3H, s), 7.48 (1H, d, J = 2.3 Hz), 7.75 (1H, d, J
= 2.3 Hz), 8.39 (3H, br s); δC (CDCl3, 100 MHz) 53.7, 111.2,
126.0, 127.9, 137.3, 153.0; HRMS m/z calcd for C6H8BrN2O
202.9815, found 202.9814; mp 148−150 °C.
N - ( 5 - B r o m o - 2 - m e t h o x y p y r i d i n - 3 - y l ) -
methanesulfonamide (24). Compound 23 (18.1 kg, 75.6
mol) was dissolved in a mixture of acetonitrile (40.0 L) and
pyridine (18.1 kg, 229 mol), and methanesulfonyl chloride
(10.8 kg, 94.3 mol) was added over 20 min. The mixture was
aged for 5 h, and then water (159 L) was added over 1 h. The
resulting slurry was aged for 2 h and filtered, and the cake was
washed with 3:1 water/acetonitrile (18 L) and dried under
vacuum at 45 °C to afford N-(5-bromo-2-methoxypyridin-3-
yl)methanesulfonamide (24) (20.0 kg, 71.1 mol, 94%) as a gray
solid. δH (CDCl3, 400 MHz) 3.05 (3H, s), 4.00 (3H, s), 6.82
(1H, s), 7.89 (1H, d, J = 2.3 Hz), 7.97 (1H, d, J = 2.3 Hz); δC
(CDCl3, 100 MHz) 40.0, 54.3, 112.0, 122.4, 128.8, 142.1,
152.8; HRMS m/z calcd for C7H10BrN2O3S 280.9590, found
280.9587; mp 136−139 °C.
N-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)pyridin-3-yl)methanesulfonamide (21). Tricyclo-
hexylphosphine (136 g, 485 mmol) and Pd2(dba)3 (166 g, 181
mmol) were dissolved in degassed toluene (17 L), and the
solution was heated to 45 °C for 45 min. The resultant solution
was added to a mixture of 24 (17.0 kg, 60.5 mol),
bis(pinacolato)diboron (18.4 kg, 72.5 mol), and potassium
acetate (11.9 kg, 121 mol) in degassed toluene (170 L) at 90
°C, and the obtained mixture was aged for 20 h. The reaction
mixture was cooled to 50 °C and filtered, washing the cake with
toluene (34 L). The resultant solution was distilled to 85 L (70
mbar, 40 °C) and cooled to 20 °C. To the resulting slurry was
added heptane (85 L) over 30 min, and then the slurry was
aged for 13 h, filtered, and washed with 1:1 toluene/heptane (2
× 17 L). The solid was dried under vacuum at 50 °C (21.6 kg,
65.8 mol, quant). A portion of the crude product (1.01 kg) was
recrystallized from 2-propanol (4.1 L), dissolving at 75 °C and
then cooling to 20 °C over 2 h and aging for 90 min. Filtration,
washing with 2-propanol (2 × 1 L), and drying at 50 °C in
vacuo afforded N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)pyridin-3-yl)methanesulfonamide (21) (710 g,
2.16 mol, 76% with respect to 24) as a white crystalline solid.
δH (CDCl3, 400 MHz) 1.32 (12H, s), 3.01 (3H, s), 4.03 (3H,
s), 6.71 (1H, br s), 8.04 (1H, d, J = 1.5 Hz), 8.31 (1H, d, J = 1.5
Hz); δC (CDCl3, 100 MHz) 24.8, 39.7, 54.1, 84.0, 120.7, 133.2,
149.4, 156.5 (no signal for C−B carbon); HRMS m/z calcd for
C13H22BN2O5S 329.1337, found 329.1336; mp 146−148 °C.
Potassium (6-Methoxy-5-(methylsulfonamido)-
p y r i d i n - 3 - y l ) t r i fl u o r o b o r a t e ( 2 7 ) . T r i s -
(dibenzylideneacetone)dipalladium (16.6 g, 18.1 mmol) and
tricyclohexylphosphine (25.0 mg, 89.1 mmol) were combined
in degassed 1,4-dioxane (2.5 L), and the mixture was aged for 1
h at 20 °C. The resultant orange solution was added to a
suspension of 24 (499 g, 1.77 mol), bis(pinacolato)diboron
(498 g, 1.96 mol), and potassium acetate (362 g, 3.69 mol) in
degassed 1,4-dioxane (8.0 L) at 100 °C, and the mixture was
aged for 1 h. The mixture was cooled to 20 °C, aged for 1 h,
and filtered, washing with 1,4-dioxane (3 L), and the resultant
solution was distilled down to 10 volumes (120 mbar, 50 °C)
and then cooled to 20 °C. Water (3 L) was added, followed by
potassium bifluoride (555 g, 7.11 mol), and the mixture was
stirred for 1 h at 20 °C. The aqueous layer was decanted, and
the organic fraction was filtered to remove further inorganics,
washing the solids with 9:1 1,4-dioxane/water (2 L). The
filtrate was concentrated and azeo-dried by distillation. Put-and-
take distillations, charging 1,4-dioxane and then distilling (250
mbar, 60 °C) to 5 L, were repeated until <0.5% w/w water
remained (checked by Karl Fischer titration). The mixture was
aged at 20 °C for 1 h and then filtered, and the cake was
washed with 1,4-dioxane (2 × 1 L) and tert-butyl methyl ether
(2 × 1 L) and then dried in vacuo at 60 °C to afford potassium
(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)trifluoroborate
(27) (708 g, 69% pure by NMR assay using 1,4-
dimethoxybenzene as an internal standard, 1.59 mol, 90%
corrected yield). δH (CDCl3, 400 MHz) 2.88 (3H, s), 3.82 (3H,
s), 7.45 (1H, s), 7.78 (1H, s); δC (CDCl3, 100 MHz) 39.9, 52.7,
120.8, 136.4, 144.5, 155.6 (no signal for C−B carbon); HRMS
m/z calcd for C7H9BF3KN2O3 308.0016, not found; however,
the trifluoroborate salt hydrolyzes to the boronic acid on the
LC−MS column, HRMS m/z calcd for C7H12BN2O5S
247.0554, found 247.0549; mp 169−171 °C.
4-((2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-
oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine (19).
2,6-cis-Dimethylmorpholine (17) (178 mL, 1.45 mol) and
triethylamine (200 mL, 1.43 mol) were added sequentially to a
solution of 3 (587 g, 92% w/w assay, 1.19 mol), in acetone (4.7
L) at 20 °C. After 30 min, water (4.7 L) was added over 10
min, and the resultant slurry was aged for a further 1 h and then
filtered. The cake was washed with 2:1 water/acetone (2 × 1.2
L) and dried in vacuo at 45 °C. The dried solid was dissolved in
DMSO (5.8 L) at 75−80 °C and after hot filtration was cooled
to 20 °C over 3 h, aged at 20 °C for 90 min, and filtered. The
cake was washed with DMSO (860 mL) followed by 2:1 water/
acetone (2 × 1.2 L) and dried in vacuo at 45 °C to afford 4-((2-
(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)-
methyl)-cis-2,6-dimethylmorpholine (19) (476 g, 0.977 mol,
82%) as a pale-yellow solid. δH (CDCl3, 400 MHz) 1.16 (6H, d,
J = 6.3 Hz), 1.86 (2H, app. t, J = 10.6 Hz), 2.76 (2H, dd, J =
10.6, 1.8 Hz), 3.67 (2H, s), 3.70 (2H, dqd, J = 10.6, 6.3, 1.8
Hz), 7.15 (1H, s), 7.50 (2H, app. t, J = 8.1 Hz), 7.61 (1H, tt, J =
8.1, 1.3 Hz), 7.97 (1H, d, J = 1.5 Hz), 8.02 (2H, dd, J = 8.1, 1.3
Hz), 8.32 (1H, s), 8.93 (1H, s); δC (CDCl3, 100 MHz) 19.1,
52.4, 59.0, 71.6, 114.5, 121.2, 121.6, 123.2, 127.7, 127.9, 129.4,
134.5, 135.8, 137.2, 141.2, 141.6, 149.6, 158.7; HRMS m/z
calcd for C23H24ClN4O4S 487.1201, found 487.1192; mp 164−
167 °C.
N-(5-(4-(5-((cis-2,6-Dimethylmorpholino)methyl)-
oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl)-2-me-
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thoxypyridin-3-yl)methanesulfonamide (26). Palladium
acetate (4.25 g, 18.9 mmol) and tricyclohexylphosphine (10.6
g, 37.8 mmol) were combined in degassed 2-propanol (2.3 L)
at 20 °C, and the mixture was stirred for 1 h. The resultant
yellow solution was added to a stirred suspension of 19 (460 g,
0.94 mol), 21 (341 g, 1.04 mol), potassium phosphate (241 g,
1.14 mol), and potassium bifluoride (162 g, 2.07 mol) in a
mixture of degassed 2-propanol (2.3 L) and water (2.3 L) at 80
°C. The resulting mixture was aged for 2.5 h and then cooled to
30 °C over 1 h, and water (2.3 L) was added. The slurry was
aged at 20 °C for 1 h and filtered, and the cake was washed with
1:1 2-propanol/water (2 × 0.92 L) and dried in vacuo at 60 °C
to afford N-(5-(4-(5-((cis-2,6-dimethylmorpholino)methyl)-
oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl)-2-methoxy-
pyridin-3-yl)methanesulfonamide (26) (611 g, 0.94 mol, 99%)
as an off-white solid. δH (CDCl3, 400 MHz) 1.01 (6H, d, J = 6.3
Hz), 1.73 (2H, app. t, J = 10.6 Hz), 2.76 (2H, dd, J = 10.6, 1.8
Hz), 3.14 (3H, s), 3.54 (2H, dqd, J = 10.6, 6.3, 1.8 Hz), 3.70
(2H, s), 4.02 (3H, s), 7.35 (1H, s), 7.61 (2H, app. t, J = 7.6
Hz), 7.74 (1H, tt, J = 7.6, 1.2 Hz), 8.03 (1H, d, J = 2.3 Hz),
8.04 (2H, dd, J = 7.6, 1.2 Hz), 8.10 (1H, d, J = 1.2 Hz), 8.36
(1H, s), 8.46 (1H, d, J = 2.3 Hz), 8.95 (1H, d, J = 1.2 Hz), 9.44
(1H, br s); δC (CDCl3, 100 MHz) 18.8, 40.8, 51.2, 53.9, 58.2,
70.9, 111.6, 120.9, 121.0, 121.4, 121.7, 127.3, 127.7, 128.6,
129.9, 130.9, 135.2, 136.1, 138.9, 141.1, 141.2, 141.5, 149.9,
156.8, 158.3; HRMS m/z calcd for C30H33N6O7S2 653.1847,
found 653.1832; mp 214−216 °C.
N-(5-(4-(5-((cis-2,6-Dimethylmorpholino)methyl)-
oxazol-2-yl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-
methanesulfonamide (2). To a suspension of 26 (596 g,
0.913 mol) in water (3.8 L) was added aqueous sodium
hydroxide (5 M, 715 mL, 3.58 mol) over 20 min, and the
mixture was stirred at 20 °C for 3 h. Propionitrile (2.55 L) was
added, and the mixture was allowed to settle, after which the
organic fraction was separated and discarded. The aqueous
phase was adjusted from pH 10 to 6 with 2 M hydrochloric acid
(1.4 L), and 2-methyltetrahydrofuran (4.8 L) was added. The
organic phase was collected, and the aqueous phase was re-
extracted with 2-methyltetrahydrofuran (4.8 L). The combined
organics were washed with water (1.2L) and distilled down to
2.4 L (100 mbar, 25 °C). The solvent was swapped to EtOAc
by successive distillations and EtOAc additions, and then the
volume was adjusted to 4.8 L by addition of further EtOAc.
Crystallization was induced by seeding at 60 °C, aging for 1 h,
cooling to 20 °C over 2 h, and aging for a further 16 h. The
mixture was filtered, and the cake was washed with EtOAc (2 ×
1.2 L) and dried in vacuo at 45 °C to afford N-(5-(4-(5-((cis-
2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1H-indazol-6-yl)-
2-methoxypyridin-3-yl)methanesulfonamide (2) (405 g, 0.790
mol, 87%) as a white solid. δH (CDCl3, 400 MHz) 1.03 (6H, d,
J = 6.3 Hz), 1.77 (2H, app. t, J = 10.6 Hz), 2.86 (2H, dd, J =
10.6, 2.0 Hz), 3.12 (3H, s), 3.57 (1H, dqd, J = 10.6, 6.3, 2.0
Hz), 3.72 (2H, s), 4.00 (3H, s), 7.34 (1H, s), 7.87 (1H, s), 7.93
(1H, d, J = 1.5 Hz), 8.00 (1H, d, J = 2.3 Hz), 8.41 (1H, d, J =
2.3 Hz), 8.58 (1H, s), 9.37 (1H, br s), 13.47 (1H, br s); δC
(CDCl3, 100 MHz) 18.9, 40.7, 51.3, 53.8, 58.3, 70.9, 110.0,
117.9, 118.3, 119.6, 121.4, 127.4, 129.5, 130.8, 133.6, 134.8,
140.8, 141.1, 149.1, 152.2, 159.8; HRMS m/z calcd for
C24H29N6O5S 513.1915, found 513.1906; mp 205−207 °C.
*E-mail: michael.r.webb@gsk.com.
ORCID
Michael R. Webb: 0000-0001-9681-169X
Notes
The authors declare no competing financial interest.
†R.N.B., L.E.V., and M.D.W. are former GSK employees.
ACKNOWLEDGMENTS
■
We thank the entire project team for their support of this work,
in particular Laura Mace and Andrew Dominey for valuable
chemistry discussions and Chris McKay, Keith Meaney, and
Marina Duffy for pilot-plant support.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: robert.n.bream@gmail.com.
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DOI: 10.1021/acs.oprd.8b00006
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
report using tartaric acid and KF to induce a precipitation-driven
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(21) Suzuki coupling of 29 and 20 using catalyst 5, NaHCO3, IPA,
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(23) Reactions carried out with KHF2 resulted in severely etched
glassware. Pilot-plant-scale reactions were carried out in Hastelloy
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(24) Menzel, K.; Machrouhi, F.; Bodenstein, M.; Alorati, A.; Cowden,
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DOI: 10.1021/acs.oprd.8b00006
Org. Process Res. Dev. XXXX, XXX, XXX−XXX