Early Development Scale-Up of a Structurally-Challenging 5-Lipoxygenase Activating Protein (FLAP) Inhibitor

Article abstract of DOI:10.1021/acs.oprd.7b00202

A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling.

Full text of DOI:10.1021/acs.oprd.7b00202

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Communication
Early Development Scale-Up of a Structurally-Challenging
5-Lipoxygenase Activating Protein (FLAP) Inhibitor
Jason Alan Mulder, Joe Gao, Keith R. Fandrick, Xingzhong Zeng, Jean-Nicolas Desrosiers, Nitinchandra
Dahyabhai Patel, Zhibin Li, Sonia Rodriguez, Jon C Lorenz, Jun Wang, Shengli Ma, Daniel R Fandrick, Nelu
Grinberg, Heewon Lee, Todd Bosanac, Hidenori Takahashi, Zhidong Chen, Alessandra Bartolozzi, Peter
Nemoto, Carl A. Busacca, Jinhua J. Song, Nathan Yee, Paige Erin Mahaney, and Chris H. Senanayake
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00202 • Publication Date (Web): 30 Jun 2017
Downloaded from http://pubs.acs.org on June 30, 2017
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Early Development ScaleꢀUp of a Structurallyꢀ
Challenging 5ꢀLipoxygenase Activating Protein (FLAP)
Inhibitor
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Jason A. Mulder, * Joe Gao, Keith R. Fandrick,ⅎ Xingzhong Zeng, JeanꢀNicolas Desrosiers,č
Nitinchandra D. Patel, Zhibin Li,‡ Sonia Rodriguez, Jon C. Lorenz, Jun Wang, Shengli Ma,§ Daniel R.
Fandrick, Nelu Grinberg,£ Heewon Lee, Todd Bosanac,† Hidenori Takahashi,†€ Zhidong Chen,†¤
Alessandra Bartolozzi,† Peter Nemoto, †¥ Carl A. Busacca, Jinhua J. Song, Nathan K. Yee, Paige E.
Mahaney,† and Chris H. Senanayake
Chemical Development, U.S., Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd.,
Ridgefield, CT 06877, United States
† Medicinal Chemistry, U.S., Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd.,
Ridgefield, CT 06877, United States
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TABLE OF CONTENTS GRAPHIC:
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KEY WORDS: quaternary, SuzukiꢀMiyaura, FLAP, resolution
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ABSTRACT:
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A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scaleꢀup
and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing
supercritical fluid chromatography (SFC) separation) for expedient access to the key structural
component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring,
condensation to form the 1,2,4ꢀoxadiazole ring, and an efficient SuzukiꢀMiyaura coupling.
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INTRODUCTION
Cardiovascular disease impacts a large number of patients today and the impact is only expected to
grow as the median age in developed countries continues to rise.1 Therefore the development of
effective new treatments for cardiovascular diseases such as atherosclerosis is truly needed. There is
evidence that one effective mode of treating such inflammatoryꢀbased diseases is by inhibition of the
leukotriene (LT) biosynthesis pathway.2 5ꢀLipoxygenaseꢀactivating protein (FLAP) inhibitors have
been shown to limit plaque growth3 and to affect biomarkers of atherosclerosis.4 Compound 1 (Figure
1) is a candidate under development as a FLAP inhibitor.5
Process development chemists must always balance the following two key deliverables: expedient
delivery of drug substance to support development, and delivery of a scalable process amenable for
commercial manufacture. We have previously described several scaleꢀup strategies toward 1,6,7,8 as
well as a stereoselective total synthesis9 of 1 via boronate rearrangement ꢀ a potential commercial route
for 1.
Herein we focus on the early process work that led to the first scalable process of this
challenging molecule in our labs which enabled advancement of the molecule through early
development by rapidly providing multiꢀkilogram quantities of drug substance for early toxicological
and clinical studies, allowing space for the development of potential commercial routes.
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Figure 1. FLAP inhibitor 1.
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RESULTS AND DISCUSSION
Discovery Synthesis of 1.
The strategy developed by the Discovery group5,10 for the target 1 (Scheme 1) was short and convergent,
where the molecule was strategically disconnected via the 1,2,4ꢀoxadiazole ring. The synthesis was
well suited for rapidly exploring synthetic space, but for the delivery of kilogram quantities of drug
substance for development, several key issues needed to be resolved quickly. The cyanation reaction (3
to 4) was not robust and proceeded in low yield which varied between 23 and 47% with the concurrent
formation of impurities requiring extensive chromatography to purge. Furthermore, the racemate was
subsequently separated using chiral supercritical fluid chromatography (SFC)11 which is not preferred
for large scale synthesis. The conversion of nitrile 7 to amidoxime 8 held additional liabilities. Thermal
studies confirmed the reaction conditions12 using excess NH2OH in refluxing ethanol were potentially
explosive and the reaction produces a high level of amide hydrolysis byꢀproduct. In addition, the key
SuzukiꢀMiyaura 13 coupling reaction would require optimization in order to achieve a robust and
efficient synthesis of the drug candidate.
Scheme 1. Discovery Synthesis of 1 and Shortcomings of the Synthesis for Scaleꢀup
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A Resolution Strategy.
Our efforts focused primarily on synthesis of nitrile 5; a resolution strategy to establish the chiral
quaternary center avoids the SFC chiral separation and its corresponding throughput bottleneck (Scheme
2). After failed initial attempts to resolve (R)ꢀ amidoximes 8 or 15 (Scheme 7) from their racemic
mixtures, we targeted carboxylic acid 9, derived from alcohol 3, as a candidate for diastereomeric salt
resolution (Scheme 3).
Scheme 2. Assembly Strategy
Oxadiazole
Formation
N
Suzuki-
Resolution
Miyaura
N
N
N
O
CO2H
OH
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CN
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Alkylation
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Br
Br
Br
H2N
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Racemic Acid Synthesis.
Tertiary alcohol 3 was efficiently and costꢀeffectively produced by reaction of the requisite 4ꢀ
bromophenyl Grignard14 reagent, generated in situ from 1,4ꢀdibromobenzene using the PrMgClꢀLiCl
i
complex,15 with 1ꢀcyclopropylethanꢀ1ꢀone in high yield. Alcohol 3 was used directly in the subsequent
cyanation. The low purity observed for nitrile 4 in the Discovery route was likely due to inefficient
trapping of the carbocation in the cyanation reaction. Conversely, nearly quantitative yield of 4 could
be achieved by premixing the tertiary alcohol 3 with excess TMSCN and slowly adding BF3ꢀOEt216 to
the mixture at low temperature. Since this process was telescoped until isolation of 9ꢀDCA (the first
solid) it was essential that formation of 4 be clean and high yielding.
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The hydrolysis of racemic nitrile 4 with potassium hydroxide under pressure (145 °C, 9 bar) provided
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carboxylic acid 9.17 Acid 9 was isolated as its dicyclohexylammonium (DCA) salt since the free acid
could not be isolated as a solid.18 More than 350 kg were produced using this process to provide 9ꢀ
DCA in an overall 65% yield (4 steps) from cyclopropyl methyl ketone and 1,4ꢀdibromobenzene.
Scheme 3. Synthesis of Quaternary Acid 11ꢀDNP
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Resolution of Racemic Acid 9.
A variety of chiral amines were tested for the resolution, and ultimately a robust process was
developed using (1R,2R)ꢀ1,3ꢀdihydroxyꢀ1ꢀ(4ꢀnitrophenyl)propanꢀ2ꢀamine (10, or DNP) in 2ꢀpropanol.
The resolved acid was isolated consistently as the DNP salt (11ꢀDNP) using temperature cycling to
achieve good crystallization control. A total of 46.5 kg of 11ꢀDNP was produced in a combined yield of
28ꢀ32% with >99% ee (after two recrystallization enrichments). Unfortunately, all efforts to resolve
racemic carboxylic acid 9 directly after the hydrolysis as the 11ꢀDNP salt (avoiding the intermediate
DCA isolation) led to lower overall recoveries (~20% overall yield), mostly due to higher mother liquor
losses.
Amidoxime Formation.
Chiral nitrile 5 was obtained by a telescopic sequence (Scheme 4). The “realꢀtime” IR trace for the
transformation from acid 11 to acid chloride 12 to amide 13 is shown in Figure 2. While the nitrile IR
signal is difficult to monitor, since it is very week, the final dehydration step could be followed easily by
the nearly instantaneous disappearance of the amide IR signal (~1670 cmꢀ1) upon addition of TFAA and
pyridine. Concomitant HPLC monitoring of “in process” samples was conducted for this campaign,
but with calibration, IR could serve as the sole In Process Testing (IPT) analytical technique for this
reaction sequence.
Scheme 4. Formation of Chiral Nitrile 5
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OH
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-O
NH3
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2) SOCl2
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TFAA, Py, Toluene
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Figure 2. In situ IR trace of acid to amide conversion.
We sought to avoid the unsafe12 process conditions (excess hydroxylamine in refluxing ethanol) used
previously for conversion of the nitrile to amidoxime (7 to 8 in Scheme 1). So the amidoxime
functionality in 15 was installed in a stepꢀwise manner via intermediate oxime 14 (Scheme 5). A Dibalꢀ
H reduction of nitrile 5 to the aldehyde was followed by oxime condensation, which could be
accomplished safely at 0 °C. Since a rapid exotherm was observed during the HCl quench of DibalꢀH,
with localized hot spots that led to formation of the amine overꢀreduction side product; we strongly
recommend the reverse quench as a preferred alternative for future scaleꢀup. The amidoxime was then
formed from 14 by a safe twoꢀstep operation, via chloroꢀoxime formation using NCS and catalytic acid,
followed by ammonia treatment.9,19 After a subsequent recrystallization from toluene/heptane, 22.9 kg
(in 2 batches) of amidoxime 15 was isolated in 75% combined yield (98.9% HPLC purity, 97.3 wt %,
99.4% ee) based on the assay of crude 14. The overall yield from solid 11ꢀDNP to solid 15 over 8
operations was 59%.
Scheme 5. Formation of Amidoxime 15
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We initially pursued a strategy of oxadiazole formation (17) between 15 and pyrazole acid 16,
followed by SuzukiꢀMiyaura coupling with boronate 6 (Scheme 6); however, this strategy required high
palladium loadings (up to 9 mol%) and led to several issues8 which provided the motivation to change
the endgame. We decided to move the coupling one step upstream in the synthetic sequence; providing
more opportunities for palladium removal prior to the final API isolation. We also removed dba from
the Pd source due to dbaꢀrelated impurity8 formation.
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Scheme 6. First Development Strategy Toward Synthesis of 1:
Synthesis Completion.
Fortunately the isolable solid amidoxime 15 proved to be a very competent coupling partner with
boronate 69, 20 (Scheme 7). The SuzukiꢀMiyaura coupling could be run with low catalyst loadings of
0.05 to 0.2 mol% Pd(TFA)221 with the patentꢀfree FcP(tꢀBu)2ꢀHBF4 ligand, which has been a privileged
ligand for SuzukiꢀMiyaura couplings in our labs. Upon reaction completion, Nꢀacetyl cysteine22 was
added to the reaction mixture to reduce the palladium level and the product precipitated from the
reaction mixture providing amidoxime 8 (22.7 kg in 2 batches) in 95% yield with >99% HPLC purity.
Scheme 7. Synthesis of 1
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Oxadiazole 18 was formed from amidoxime 8 and CDIꢀactivated acid 16 in DMF (Scheme 7). The
elimination of an intermediate aminal to form the oxadiazole ring was achieved thermally (without
addition of acid), but required high temperature (100 °C). The optimal charges of CDI and 16 were 1.05
and 1.10 equivalents, respectively. A deviation from these ratios was detrimental to the reaction,
causing impurity formation. THF functioned exclusively as a carrier solvent for reagent addition; it was
then removed by distillation as the reaction temperature was ramped eventually to 100 °C. This strategy
permitted only 2.5 volumes of the reaction solvent DMF to be used, which eliminated the need for any
back extraction of the aqueous layer during workꢀup.23
Only after several months of project work, were we finally able to obtain oxadiazole 18 in crystalline
form from a sample which had spontaneously crystallized. These valuable seeds were used to
ultimately facilitate the final crystallization of 18, providing a valuable additional purification prior to
the API step. This seeding strategy was employed on scaleꢀup leading to isolation of 22 kg of
oxadiazole 18 in two batches in a combined 86% yield with 99.8% HPLC purity at <10 ppm Pd
(obtainable with the combination of carbon treatment and crystallization). A solid form of 18 could not
be isolated in the absence of seeds regardless of substrate purity or the solvent system employed.
Alkylation of oxadiazole 18 was achieved by heating a mixture of 18, chloride 19,24 and DBU at 45
°C for 2 h in DMF. These homogenous conditions provided a dramatic rate increase compared with the
K2CO3/THF conditions employed in the Discovery route. Following an aqueous workꢀup, crude 1 was
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isolated from IPAc. A final recrystallization from ethanol/water provided purified 1 (83% for 2 steps,
>99% HPLC purity) with <5 ppm palladium.
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CONCLUSION
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A practical and efficient resolutionꢀbased synthesis of FLAP inhibitor 1 was developed that more than
doubled the overall yield of the Discovery synthesis. An optimized synthesis of carboxylic acid 9 was
effected from inexpensive cyclopropyl methyl ketone and 1,4ꢀdibromobenzene. Resolution of
carboxylic acid 9 as its (1R,2R)ꢀ1,3ꢀdihydroxyꢀ1ꢀ(4ꢀnitrophenyl)propanꢀ2ꢀamine (DNP) salt provided
expedient and ready access to the challenging chiral quaternary center as an alternative to using SFC
chromatography. A safe, stepꢀwise alternative process was implemented for the amidoxime synthesis
via a chloroꢀoxime intermediate to avoid the potentially explosive conditions of excess hydroxylamine
in refluxing ethanol. A highly efficient SuzukiꢀMiyaura coupling of amidoxime 15 and boronate 6 was
implemented which reduced palladium loading from ~10 mol% down to <0.2 mol%. This strategy was
an effective fitꢀforꢀpurpose route which provided drug substance for early development work packages.
EXPERIMENTAL SECTION
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1ꢀ(4ꢀBromophenyl)ꢀ1ꢀcyclopropylethanꢀ1ꢀol (3). Turbo Grignard (iꢀPrMgClꢀLiCl) solution in THF
(443 kg, 14.6 wt %, 629 mol, 1.2 equiv) was added to a solution of 1,4ꢀdibromobenzene (125 kg, 530
mol, 1 equiv) in THF (220 kg) at –4 to 0 °C over 70 min. The solution was warmed to 20 °C and stirred
for 22 h, then cooled to 0 °C. Cyclopropylmethylketone (48 kg, 571 mol, 1.08 equiv) was added to the
reaction mixture at 0–20 °C. The reaction mixture was stirred for 3 h at 20 °C. The mixture was diluted
with heptane (428 kg), cooled to 0 °C, and transferred to a new reactor (50 kg of THF was used as a
rinse). An 5% aqueous solution of citric acid (673 kg) was cooled to 0 °C and charged to the Grignard
solution over 1.5 h maintaining a temperature of 0–20 °C. At 20 °C the biphasic mixture was stirred for
20 min, the pH was 8–9 so 3 kg additional citric acid was added to bring the pH to 5). The layers were
separated and the aqueous layer was removed. The organic layer was washed with 5% aqueous
NaHCO3 solution (312 kg) and 5% aqueous NaCl solution (312 kg). The organic layer was
concentrated at 35 °C (675–600 torr) and then filtered over Celite (5 kg). The filter cake was rinsed
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with heptane (38 kg). The organic layer was further concentrated at 35 °C (150–40 torr) to give
carbinol 3 as a pale yellow oil (160 kg, 86% yield, 82.5 wt %, 90 LCAP). 1H NMR (400 MHz, CDCl3) δ
0.3ꢀ0.45 (m, 3H), 0.45ꢀ0.6 (m, 1H), 1.1ꢀ1.3 (m, 1H), 1.46 (s, 3H), 7.40 (d, J = 8 Hz, 2H), 7.45 (d, J = 8
Hz, 2H). Analytical data consistent with literature.25
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2ꢀ(4ꢀBromophenyl)ꢀ2ꢀcyclopropylpropanenitrile (4). A mixture of carbinol 3 (33.4 kg, 68.9 wt %,
95.4 mol, 1 equiv), TMSCN (23.8 kg, 240 mol, 2.5 equiv), and dichloromethane (288 kg) were cooled
to –72 °C and a BF3ꢀEt2O (12.2 kg, 86.0 mol, 0.9 equiv) solution in CH2Cl2 (10 kg) was added over 20
min maintaining an internal temperature of –75 to –65 °C. The mixture was warmed over 1 h to –20 °C
and stirred for 30 min, then warmed over 2 h to 20 °C. Upon completion, the reaction mixture was
added to an aqueous 2N NaOH solution (154 kg, 333 mol, 3.5 equiv) maintaining internal temperature
of ~20 °C. The biphasic mixture was stirred for 1 h and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 × 122 kg). The combined 3 organic layers were washed with aqueous 2N
NaOH solution (2 × 154 kg) and then with water (2 × 91 kg). The organic layer was concentrated at 40
°C (450–150 torr) and filtered to remove solid bodies. The filter was washed with heptane (5 kg) and
the combined organic layers were concentrated at 40 °C (225–40 torr) to yield nitrile 4 as a yellow oil
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(29.8 kg, 94% yield, 75 wt %, 84.6 LCAP). H NMR (400 MHz, CDCl3) δ 0.45ꢀ0.75 (m, 4H), 1.15ꢀ1.3
(m, 1H), 1.73 (s, 3H), 7.39 (d, J = 8.5 Hz, 2H), 7.51 (d, J= 8.5 Hz, 2H). Analytical data consistent with
literature.5
2ꢀ(4ꢀBromophenyl)ꢀ2ꢀcyclopropylpropanoic acid (9). A solution of nitrile 4 (50.3 kg, 70 wt %, 140.7
mol, 1 equiv) was solvent switched from heptane to 1ꢀpropanol with 3 cycles of the following: 34 L 1ꢀ
propanol was charged and an equal volume of distillate was collected via distillation at 45 °C (150–30
torr). After the distillation cycles, 42 kg (52 L) of 1ꢀpropanol was charged to provide a 37 wt %
solution of 4 in 1ꢀpropanol. 50 wt % Aqueous KOH (110 kg, 980 mol, 7 equiv) and water (7 kg) were
added to the solution. The mixture was stirred for 10–12 h at 145 °C in an autoclave (maximum
pressure achieved was 9 bar). The reaction mixture was cooled to 25 °C and diluted with heptane (71
kg) and water (159 kg). Conc. HCl (140 kg) was added at 0 °C until pH ≤ 1. The aqueous layer was
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removed. Heptane (63 kg) and 1M aq HCl (132 kg) were added to the organic layer and the aqueous
layer was separated. The organic layer was washed with water (105 kg), filtered over Celite® (3 kg),
and the filter residue was washed with heptane (18 kg). The organic layer was concentrated to
minimum volume at 45 °C (75 torr) to yield acid 9 as a yellow oil (52.4 kg, 94.8% yield, 68.5 wt %,
84.6 LCAP).
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Dicyclohexylammonium 2ꢀ(4ꢀbromophenyl)ꢀ2ꢀcyclopropylpropanoate (9ꢀDCA). A solution of 9
free acid (111 kg, 67 wt %, 279 mol, 1 equiv) was diluted with heptane (514 kg) and heated to 60 °C.
Dicyclohexylamine (56 kg) was added over 1 h. The formed suspension was stirred for 1 h at 60 °C,
then cooled over 2 h to 20 °C and held for 1 h at this temperature. The suspension was filtered and the
filter cake was washed with heptane (96 kg). The product was dried in an oven (45 °C) to yield acid salt
1
9ꢀDCA as an offꢀwhite solid (117 kg, 92% yield, ~100 wt %, 98.8 LCAP). H NMR (400 MHz, CDCl3)
δ 0.30–0.45 (m, 3H), 0.50–0.60 (m, 1H), 1.0ꢀ1.30 (m, 10H), 1.16 (s, 3H), 1.40–1.52 (m, 1H), 1.58–1.68
(m, 2H), 1.68–1.76 (m, 4H), 1.82–1.90 (m, 4H), 2.70–2.80 (m, 2H), 7.36 (s, 4 H). 13C NMR (100 MHz,
CDCl3) δ 1.25, 1.92, 18.79, 22.10, 24.82, 25.32, 29.78, 50.67, 52.42, 119.27, 128.90, 130.60, 147.55,
180.25. mp 168.2–170.4 °C.
Resolution
(1R,2R)ꢀ1,3ꢀDihydroxyꢀ1ꢀ(4ꢀnitrophenyl)propanꢀ2ꢀaminiumꢀ(R)ꢀ2ꢀ(4ꢀbromophenyl)ꢀ2ꢀ
cyclopropylpropanoate (11ꢀDNP).
Salt Break: To a slurry of 9ꢀDCA (50.7 kg, 98.9 wt %, 111 mol, 1 equiv) in MTBE (223 kg) was added
2 N aqueous HCl (122 kg, 222 mol, 2 equiv). The mixture was stirred for 1 h and produced a thick
slurry. The precipitated dicyclohexylammonium chloride was removed by filtering the reactor contents
(both layers). The reactor and filter cake were rinsed with MTBE (74 kg). The filtrates were returned to
a clean reactor. The bottom aqueous layer (pH = 1) was removed and the organic layer was washed
with 1 N aqueous HCl (113 kg, 111 mol, 1 equiv) then water (117 kg). The assay yield of 9 was
determined by HPLC to be 10.8 wt % (32.1 kg of 9 contained). The MTBE was then removed by
distillation at 60 °C (760–625 torr). Isopropanol (164 kg) was added to chase residual MTBE at 50–60
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°C (760–230 torr) until <0.1 GC wt % MTBE and <1 GC wt % water were achieved. IPA was added
(217 kg) to adjust the total isopropanol content to 8 L IPA per 1 kgI of 9 (from assay).
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11ꢀDNP salt formation: The IPA solution of 9 was heated to 75–80 °C to obtain a clear solution. 1R,
2Rꢀ2ꢀAminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀpropaneꢀ1,3ꢀdiol (DNP) (18.8 kg, 88.7 mol, 0.8 equiv) was charged as a
slurry in IPA (23.4 kg).I The mixture was cooled to 50 °C and a seed slurry of 11ꢀDNP (1.5 kg, >99%
ee, 0.05 equiv) in IPA (2.5 kg) was added. The batch was then cooled at a rate of 10 °C/h and a thick
slurry developed at 26 °C. Cooling was suspended and a temperature cycle was conducted. The batch
was reheated to 55 °C and aged for 2 h, it was then cooled to 20 °C over 5 h. The solid was collected by
filtration and the reactor and cake were rinsed with the filtrate to remove held up product. Finally the
filter cake was rinsed with IPA (24 kg) and spun in the centrifuge to yield 11ꢀDNP as a damp, offꢀwhite
solid (31.72 kg, 67.3 wt %, 67.9% yield, 37.7 mol of the desired isomer based on 82.7% ee). Yield is
corrected for the seed load (1.5 kg).
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I This mass was subtracted from the charge of IPA used above to reach a total isopropanol content of 8 L
per 1 kg of acid 9 AFTER addition of the resolving agent slurry.
1st Recrystallization of 11ꢀDNP: Crude 11ꢀDNP from the previous step and IPA (123.6 kg, 8 L per 1
kg 11ꢀDNP dry basis) were heated to 75 °C to obtain a clear solution. The solution was then cooled to
60 °C over 30 min and a slurry of 11ꢀDNP seeds (0.2 kg, 1 wt %; >99% ee) in IPA (1 kg) were charged.
The batch was then cooled at a rate of 10 °C/h and a thick slurry developed at 30 °C. Cooling was
suspended and a temperature cycle was conducted. The batch was reheated to 55 °C and aged for 2 h, it
was then cooled to 20 °C over 5 h. The solid was collected by filtration and the reactor and cake were
rinsed with the filtrate to remove held up product. Finally the filter cake was rinsed with IPA (20 kg)
and spun in the centrifuge to yield 11ꢀDNP (23.44 kg, 97.8% ee) as a wet, offꢀwhite solid.
2nd Recrystallization of 11ꢀDNP: A slurry of 11ꢀDNP wet cake from above (23.44 kg, 97.8% ee) and
IPA (110 kg) were heated to 78 °C to obtain a clear solution. The solution was then cooled to 60 °C
over 30 min. and then a slurry of 11ꢀDNP seeds (0.2 kg, 1 wt %; >99% ee) in IPA (1 kg) were charged.
The batch was then cooled at a rate of 10 °C/h and a thick slurry developed at 23 °C. Cooling was
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suspended and a temperature cycle was conducted. The batch was reheated to 55 °C and aged for 2 h, it
was then cooled to 20 °C over 5 h and held at 20 °C for 36 h. The solid was collected by filtration and
the reactor and cake were rinsed with the filtrate to remove held up product. Finally, the filter cake was
rinsed with IPA (20 kg) and spun in the centrifuge and dried at 38 °C (40 torr) to yield 11ꢀDNP as a
white solid (18.8 kg, 31% yield from 9ꢀDCA, 99 wt %, 99.5% ee). Note: % yield is corrected for the
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total seed load (1.9 kg) over 3 operations. H NMR (400 MHz, DMSOꢀd6) δ 0.2–0.3 (m, 1H), 0.3–0.38
(m, 1H), 0.38–0.5 (m, 2H), 1.10 (s, 3H), 1.35–1.45 (m, 1H), 2.91 (q, J = 8 Hz, 1H), 3.19 (dd, J = 8, 12
Hz, 1H), 3.40 (dd, J = 4, 12 Hz, 1H), 4.75 (d, J = 8 Hz, 1H), 7.40 (d, J = 12 Hz, 2H), 7.43 (d, J = 12 Hz,
2H), 7.62 (d, J = 8 Hz, 2H), 8.19 (d, J = 8 Hz, 2H). 13C NMR (100 MHz, DMSOꢀd6) δ 1.37, 3.71,
18.56, 21.61, 49.62, 58.39, 60.78, 70.76, 118.78, 123.13, 127.89, 128.90, 130.52, 146.58, 146.64,
151.16, 177.90. mp 147.2–151.2 °C.
(R,Z)ꢀ2ꢀ(4ꢀBromophenyl)ꢀ2ꢀcyclopropylꢀN'ꢀhydroxypropanimidamide (15). The acid salt 11ꢀDNP
(22.06 kg, 45.8 mol, 1 equiv), toluene (191 kg), and 1 N aqueous HCl (93 kg, 91.7 mol, 2 equiv) were
o
combined at 20 C. The batch was agitated for 1 h and after settling the aqueous layer was removed.
The toluene layer was washed with water (44 kg). Aqueous layers were pH = 1. The batch was
distilled to minimal volume at 45–50 oC (80 torr) achieving a KF of 26 ppm. Additional toluene (61 kg)
was added to bring the batch to 3 L toluene per 1 kg 11ꢀDNP (KF 310 ppm). At 22 oC N, DMF (163 g,
2.3 mol, 0.05 equiv) and thionyl chloride (7.54 kg, 59.5 mol, 1.3 equiv) were charged and the batch was
heated to 47 oC and held for 1 h. (Note: The acid chloride is very air / water sensitive, conversion was
measured based on the benzyl amide product formed by addition of dry benzylamine to the reaction
mixture, which was then diluted with dry ACN for analysis.) Vacuum was applied (75 torr) to affect
o
removal of ~50 L of distillate. Toluene (57 kg) was added and the batch was cooled to 10 C.
Ammonia gas (1.96 kg, 115 mol, 2.5 equiv) was charged subꢀsurface over 1.5 h maintaining an internal
o
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maximum temperature of 20 C. After an additional 0.5 h, vacuum was applied at 20 C for 1 h to
o
remove residual ammonia. The batch was cooled to 0 C and pyridine (7.24 kg, 91.6 mol, 2 equiv) was
charged, followed by TFAA (15.3 kg, 73.3 mol, 1.6 equiv) over 30 min, maintaining a temperature of
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o
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10–15 C. After an additional 30 min at 20 C the batch was washed sequentially with 10% aqueous
Na2CO3 (96.8 kg, 91.6 mol, 2 equiv), followed by 1 N aqueous HCl (44 kg, 44 mol, ~1 equiv) and water
(44 kg). The batch was distilled to minimal volume at 45–50 oC (275 torr) and cooled to 20 oC to yield
a 45 wt % solution of nitrile 5 in toluene (22.1 kg, 40.0 mmol, 91.7 LCAP). Toluene was added (16 kg)
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(KF <200 ppm). The solution of nitrile 5 was cooled to –15 C and DIBALꢀH (27.3 kg, 25 wt % in
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toluene, 48 mol, 1.2 equiv) was charged over 1.5 h at <0 C. The batch was held at –10 C for 0.5 h,
o
then 4 N aqueous HCl (31.5 kg, 120 mol, 3 equiv) was charged over 1 h at 5–10 C. The resulting
slurry was warmed to 20 oC over 2 h and then held for 8–12 h under vigorous agitation. (The slurry may
thicken initially but should thin within one hour. Extended stirring time is required to break up
o
aluminumꢀbound species.) Toluene (26 kg) and 5% aqueous NaCl (10 kg) were charged at 20 C,
mixed with moderate agitation, and allowed to settle. After removal of the bottom aqueous phase, the
toluene phase was washed with 5% aqueous NaCl (30 kg) and then distilled to minimal stirrable volume
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at 45–50 C (50 torr). Ethanol (19.7 kg) was charged and the batch was cooled to 0 C. 50 wt %
Aqueous hydroxylamine (4 kg, 60 mol, 1.5 equiv) was added over 10 min with a temperature rise to 5
oC. The batch was warmed to 20 oC over 30 min. After addition of IPAc (61 kg) the batch was washed
o
with 5% aqueous NaCl (30 kg x 2) and distilled to minimum volume (~12 L) at 45 C (40 torr).
o
Acetonitrile (30 kg) was added and the batch was again concentrated at 45 C (40 torr) to ultimately
yield a concentrated solution of oxime 14 in ACN (25.6 kg, 38.6 mmol, 40.5 wt %, 86.5 LCAP). To
this solution was charged conc. HCl (1.93 kg, 20 mol, 0.5 equiv) at 10–20 oC. The batch was cooled to
o
5 C and a Nꢀchlorosuccinimide (5.23 kg, 40 mol, 1.05 equiv) solution in ACN (18 kg) was charged
over 30 min at 0–10 oC. (Due to stability concerns, the NCS solution should not be prepared more than
2 h before use.) 28% NH4OH (10.9 kg, 90 mol, 2.3 equiv) and water (20 kg) were charged to the
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reactor maintaining the batch temperature 20–25 C (NH4OH addition is very exothermic at the
o
beginning!). The batch was agitated at 20–25 C for 1 h. Toluene (70 kg) was charged and the batch
was washed with water (20 kg), then twice with 5% aqueous NaCl (40 kg). The batch was distilled
down to ~20 L at 45–50 oC (70 torr). Seeds of amidoxime 15 (80 g, >99% ee) were charged as a slurry
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o
in toluene (290 mL), after 1 h at 50–55 C, heptane (24 kg) was charged slowly over 1 h to the slurry
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maintaining a temperature of 50–55 C, the batch was then held at this temperature for 1 h, and cooled
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to 20–25 oC at a constant rate over 6 h. The solid was collected by filtration, the reactor and cake were
rinsed with the filtrate, and finally the collected solids were rinsed with heptane (15 kg). The solid was
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dried at 20 C (40 torr) yielding amidoxime 15 as a tan colored solid (5.86 kg, 74% yield, 98 wt %,
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99.4% ee, 98.9 LCAP). mp 118.7–120.8 °C. Analytical data consistent with literature.9
5ꢀ(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)pyrimidinꢀ2ꢀamine (6). 5ꢀBromopyrimidinꢀ2ꢀamine
(15 kg, 86 mol, 1 equiv), bis(pinacolato)diborane (24.2 kg, 95.3 mol, 1.1 equiv), potassium acetate (16.9
kg, 172 mol, 2.0 equiv), Pd2(dba)3 (80 g, 86 mmol, 0.1 mol %), and diꢀtertꢀbutylphosphinoferrocene
tetrafluoroborate [FcP(tꢀBu)2•HBF4] (72 g, 172 mol, 0.2 mol %) were charged to a reactor which was
then purged with nitrogen to O2 <0.5%. 2ꢀMeTHF (51.5 kg) ꢀ degassed with nitrogen – was charged
o
and the mixture was heated to 80 C for 3–4 h. After verification of reaction completion by HPLC
(>99% consumption of 5ꢀBromopyrimidinꢀ2ꢀamine), 2ꢀMeTHF (200 kg) was charged while adjusting
o
the reaction temperature to 55–60 C. The mixture was held at this temperature for 2–3 h with stirring.
o
The slurry was filtered through a filter paper at 55–60 C to remove inorganics, followed by a warm
(~50 oC) THF (67 kg) rinse of the reactor and filter cake. After ensuring the reaction vessel was free of
solids (rinse with 2ꢀMeTHF if necessary), the filtrate was returned to the reactor and solvent removed at
o
55 C (270 torr) to minimum stirrable volume (330 L distillate). Ethanol (59.3 kg) was added and the
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batch was distilled at 60 C (280 torr) removing ~75 L of distillate. Additional ethanol (237 kg) was
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charged and the after full dissolution at 65 C (1 h) the batch was purified by filtration through a
CUNO® (R53SP) activated carbon filter cartridge. The filtrate and the ethanol (24 kg) rinse were
o
collected in a clean reactor for the crystallization. The batch was concentrated at 55–60 C (270 torr)
removing 260 L distillate and then was cooled to 20–22 oC over 2 h, the resulting slurry was aged for 2
h, and then the solid was isolated by filtration. The reactor and cake were rinsed with ethanol (35.5 kg)
o
and then then dried at 45 C (30–40 torr) for >4 h yielding boronate 6 as offꢀwhite needles (14.75 kg,
80% yield, 97.8 wt %, 99.9 LCAP). mp 208.9–211.8 °C. Analytical data consistent with literature.20
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(R,Z)ꢀ2ꢀ(4ꢀ(2ꢀAminopyrimidinꢀ5ꢀyl)phenyl)ꢀ2ꢀcyclopropylꢀN'ꢀhydroxypropanimidamide
(8).
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Amidoxime 15 (11.32 kg, 99.2 wt %, 39.7 mol, 1 equiv), boronate 6 (11.38 kg, 51.5 mol, 1.3 equiv),
Pd(O2CCF3)2 (26 g, 78 mmol, 0.20 mol %), and diꢀtꢀbutylphosphinoferrocene tetrafluoroborate [FcP(tꢀ
Bu)2•HBF4] (37 g, 88 mmol, 0.22 mol %) were charged to the reactor. The reactor was inerted with
three vacuumꢀAr purge cycles. A degassed solution of K3PO4 (16.9 kg, 79.6 mol, 2 equiv) in water (45
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kg) and degassed IPA (44 kg) were charged and the resulting suspension was heated to 80–82 C over
45 min and held for 3–6 h. While maintaining the reaction mixture at 80–82 oC, Nꢀacetyl cysteine (1.62
kg, 9.9 mol, 0.25 equiv) in water (67.5 kg) was charged over 1 h. The resulting mixture was agitated for
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3–8 h at 80–82 C, then allowed to cool down linearly to 20 C over 4 h. The resulting crystalline
product was collected by filtration and the cake rinsed with water (34 kg) and IPAc (29 kg) yielding
amidoxime 8 as an offꢀwhite, crystalline solid (11.32 kg, 94.8% yield, 99.2 wt %, 99.8 LCAP). mp
197.3–200.8 °C. Analytical data consistent with literature.9
(R)ꢀ5ꢀ(4ꢀ(1ꢀ(5ꢀ(1HꢀPyrazolꢀ4ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)ꢀ1ꢀyclopropylethyl)phenyl)pyrimidinꢀ2ꢀ
amine (18). A solution of pyrazole acid 16 (4.5 kg, 40 mol, 1.3 equiv) in DMF (21.6 kg) was charged
o
over 10 min to a mixture of CDI (6.16 kg, 36.8 mol, 1.2 equiv) and THF (20.3 kg) at 20–22 C. The
o
batch was heated to 50–55 C and held for 0.5 h. A solution of amidoxime 8 (9.2 kg, 99.2 wt %, 30.7
mol, 1 equiv) in THF (57 kg) was added. The batch was heated and THF removed by distillation until
the internal temperature stabilized to 105 °C. The batch was maintained at this temperature for 12–20 h
and then cooled to 20–22 oC. EtOAc (115 kg) and water (64 kg) were charged to the mixture, the layers
were separated and the top organic layer was washed with water (64 kg). The organic layer was heated
to 45 °C and filtered through a CUNO® (R53SP) activated carbon filter cartridge. The filter was rinsed
with EtOAc (74 kg) and the combine filtrates were concentrated at 57 °C (350 torr) removing 330 L of
distillate. At 55–60 °C the batch was seeded with 18 (205 g) in IPAc (2 kg), held for 30 min. and IPAc
(89 kg) was charged at a constant rate over 1 h maintaining the batch temperature of 55ꢀ60 °C. The
slurry was concentrated at 57 °C (250 torr) removing 100 L of distillate. Heptane (28 kg) was charged
at a constant rate over 1 h at 57 °C. The slurry cooled to 20–22 °C over 4ꢀ6 h and held for 1 h. The
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solid was collected by filtration, and the cake was rinsed with IPAc (36 kg) then heptane (42 kg). The
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solid was dried at 60 C (25 torr) for 12 h, yielding oxadiazole 18 as an offꢀwhite solid (9.42 kg, 86%
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yield, 99.2 wt %, 99.7% ee, 99.8 LCAP). mp 186.4–190.1 °C. Analytical data consistent with
literature.9
9
(R)ꢀ2ꢀ(4ꢀ(3ꢀ(1ꢀ(4ꢀ(2ꢀAminopyrimidinꢀ5ꢀyl)phenyl)ꢀ1ꢀcyclopropylethyl)ꢀ1,2,4ꢀoxadiazolꢀ5ꢀyl)ꢀ1Hꢀ
pyrazolꢀ1ꢀyl)ꢀN,Nꢀdimethylacetamide (1). Oxadiazole 18 (11.02 kg, 99.9 wt %, 29.5 mol, 1 equiv),
DMF (31.1 kg), 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) (6.28 kg, 41.25 mol, 1.4 equiv), and 2ꢀ
chloroꢀN,Nꢀdimethylacetamide (19) (4.65 kg, 38.25 mol, 1.3 equiv). Upon complete addition of 11, the
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temperature rose to 37 C and additional heating was applied to bring the batch to 48–50 C, where it
was held for > 30 min. IPAc (38.4 kg) was charged while maintaining a batch temperature of 45–55
oC. The solution was then seeded with 1 (110 g, 1 wt %) suspended in water (550 mL) at 50–55 oC, and
held at this temperature for 30 min. Water (33 kg) was charged over 1 h, then stirred for 30 min at 50–
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55 C. A second charge of water (33 kg) was made at 45–55 C over 1 h, followed by stirring for 1 h.
Finally a third charge of water (33 kg) was made at 45–55 oC over 1 h, followed by stirring for 2 h. The
batch was cooled to 20 oC over 4 h, then held at 20 oC for 4 h. The crystalline product was collected by
filtration, the cake rinsed iteratively with water (33 kg), IPAc (29 kg), and finally heptane (23 kg) and
o
the solid dried at 55 C (35 torr) for 24 h yielding 1 as an offꢀwhite, crystalline solid (13.05 kg, 95.6%
yield, 98.6 wt %, 99.7% ee, 99.6 LCAP). Pd content was 160 ppm. Crude 1 was recrystallized from
o
ethanol/water to obtain the desired final form in 95% yield. mp 193.6–196.2 C. Analytical data
consistent with literature.9
ASSOCIATED CONTENT
Supporting Information
13
1H and C NMR data for new compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Authors
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*Email: jason.mulder@boehringerꢀingelheim.com; Telephone: 203.791.6861; Fax: 203.791.5875
Present Addresses
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ⅎ K.F.: LAM Therapeutics, 530 Old Whitfield Street, Guilford, CT 06437. keithfand@gmail.com
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J.N.D: Pfizer, 558 Eastern Point Rd, Groton, CT 06340, United States.
jeannicolasdesrosiers@hotmail.com
‡ Z.L.: Locke Lord LLP, Brookfield Place, 200 Vesey Street, 20th Floor, New York, NY 10281ꢀ2101,
United States. zhibin.li@lockelord.com
§ S.M.: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
shenglima@hotmail.com
£ N.G.: 274 Aspetuck Ridge Road, New Milford, CT 06776, United States. ngrinb3684@aol.com
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Organic Process Research & Development
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6 Zeng, X.; Gao, J.; Song, J. J.; Ma, S.; Desrosiers, J.ꢀN.; Mulder, J. A.; Rodriguez, S.; Herbage, M. A.; Haddad, N.; Qu, B.;
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8 The following referenced book chapter tells the larger story of the development of FLAP inhibitor 1: Fandrick, K.; Mulder,
J.; Desrosiers, J.ꢀN.;Patel, N.; Zeng, X.; Fandrick, D.; Busacca, C. A.; Song, J. J.; Senanayake, C. H. Development of an
Efficient Asymmetric Synthesis of the Chiral Quaternary 5ꢀLipoxygenase Activating Protein Inhibitor. In Comprehensive
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10 Takahashi, H; Bartolozzi, A.; Simpson, T. Discovery of the Novel OxadiazoleꢀContaining 5ꢀLipoxygenase Activating
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12 Bretherick, L. Bretherick's Handbook of Reactive Chemical Hazards, 4th ed.; Butterworths: Boston, 1990; 1233ꢀ1234.
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17 The use of pressure reduced the reaction time to 10ꢀ12 h from 24ꢀ72 h. While the nitrile consumption was complete after
24 h at atmospheric pressure, the conversion of the last 5ꢀ10% of intermediate primary amide to acid 9 typically required
extended reaction times.
18
The typical purity of crude 9 was ~85 LCAP. The majority of the impurities were nonꢀpolar and the DCA salt
crystallization was quite powerful leading to isolated 9ꢀDCA in >98.5 LCAP.
19 a) Liu, K.ꢀC.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916–3918; b) Menzel, K.; Machrouhi, F.; Bodenstein,
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20 For an optimized synthesis of the free boronic acid see: Patel, N. D.; Zhang, Y.; Gao, J.; Sidhu, K.; Lorenz, J.; Fandrick, K.
R.; Mulder, J. A.; Herbage, M. A; Li, Z.; Ma, S.; Lee; H. Grinberg, N., Song, J. J.; Busacca, C. A., Yee, N. K.; Senanayake,
C. H. Org. Process Res. Dev. 2016, 20, 95−99.
21 0.20 mol% was used for scaleꢀup. (compared with ~10 mol% required for the first strategy).
22 a) Villa, M.; Cannata, V. PCT Int. Appl. WO 1998/051646. b) Königsberger, K.; Chen, G.ꢀP.; Wu, R. R.; Girgis, M. J.;
Prasad, K.; Repič, O.; Blacklock, T. J.Org. Process Res. Dev. 2003, 7, 733–742.
23 No backꢀextractions were required; however, four water washes were needed to remove residual imidazole and DMF from
the organic layer.
24 Despite being an alkylating agent, alkyl chloride 19 did not raise a flag during the initial in silico genotoxicity assessment.
Because of its high water solubility and reactivity it should not remain with the product after the aqueous workꢀup, and any
carryꢀover should be removed in the EtOH/water recrystallization.
25 Olah, G. A.; Prakash, K. S.; Liang, G. J. Org. Chem. 1977, 46, 2666–2671.
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