Harnessing the Power of Catalysis for the Synthesis of CRTH2 Antagonist MK-1029

Article abstract of DOI:10.1021/acs.oprd.1c00128

The synthetic strategy utilized to prepare clinical supplies of CRTH2 antagonist MK-1029 is described. Specifically, the approach communicated is predicated on the intervention of five distinct catalytic methods, using three separate metals and an enzyme, to enable successful construction of this complex active pharmaceutical ingredient.

Full text of DOI:10.1021/acs.oprd.1c00128

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Article
Harnessing the Power of Catalysis for the Synthesis of CRTH2
Antagonist MK-1029
Rebecca T. Ruck,* Jun Pan, Rishi G. Vaswani, Birgit Kosjek, Neil A. Strotman, Chaoxian Cai,
and Guy R. Humphrey
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ABSTRACT: The synthetic strategy utilized to prepare clinical supplies of CRTH2 antagonist MK-1029 is described. Specifically,
the approach communicated is predicated on the intervention of five distinct catalytic methods, using three separate metals and an
enzyme, to enable successful construction of this complex active pharmaceutical ingredient.
KEYWORDS: catalysis, biocatalysis, Heck, N−H insertion, ketoreductase, triazole, Sonogashira
hemo-attractant receptor expressed on Th2 cells
(CRTH2) is one of two known high-affinity trans-
ketone reduction (ketoreductase), (4) Sonogashira reaction
(palladium), and (5) azide−alkyne cycloaddition (ruthenium).
We envisioned the retrosynthesis of MK-1029 as depicted in
Scheme 1, highlighting the key bond disconnections, all of
which require the use of catalytic methods. The final step is a
hydrolysis of the corresponding MK-1029 ethyl ester 2.
Generating this penultimate intermediate requires a con-
vergent click reaction between tricyclic azide 3 and terminal
alkyne 4; the 1,5-regiochemistry about the 1,2,3-triazole
moiety is noteworthy and necessitates careful selection of the
catalyst to access the desired compound. Azide 3 is envisioned
to arise from SN2 displacement of activated intermediate 5,
which itself would be derived from secondary alcohol 6. This
alcohol could be obtained by asymmetric reductioneither
chemo- or biocatalyticallyfrom the corresponding ketone 7.
This carbonyl compound is envisioned to derive from indole
diester 8 via a catalytic method, with the indole core also
formed from arene 9 and diethyl oxopimelate (10) via
catalysis. The alkyne moiety 4 maps onto a Sonogashira
coupling between 4-fluorobenzyl bromide (11) and an
acetylene derivative; for this transformation, it is critical to
ensure that the triple bond does not isomerize into conjugation
as the corresponding allene or internal alkyne.
C
membrane receptors for prostaglandin d2 (PGD2).1 It has
been found to play a role in leukocyte activation,2 with
biological data suggesting that downstream events triggered by
activation of CRTH2 through binding to PGD2 play a key role
in stimulating late-phase allergic inflammation.3 Our company
has disclosed a series of CRTH2 antagonists for the treatment
of respiratory disease, including MK-8318,4 MK-7246,5 and
MK-1029 (1)6 (Figure 1), which is the subject of this article.
Figure 1. CRTH2 antagonists from MSD.
In the forward sense, solving for the first two catalytic
transformationsto form the necessary tricyclic indole core
was critical to the success of this synthesis.8 Unsurprisingly,
these two constructions also proved to be incredibly
challenging. Our first goal was to identify an efficient method
to assemble the indole diester core. Ultimately, two approaches
were prioritized for this construction: Fischer indole synthesis
(Scheme 2A)9 and an imine-Heck reaction (Scheme 2B).10
While significant synthetic efforts were previously undertaken
for the structurally similar MK-7246,5b the presence of a
fluorine atom on the indole and a 1,5-disubstituted 1,2,3-
triazole side chain in MK-1029 necessitated the investigation of
alternative chemistry to address critical bond disconnections.
In considering a disconnection strategy for MK-1029, the
cornucopia of catalytic methods developed over the last 20
years provided a diverse toolkit that was well-suited for
developing an efficient and sustainable synthesis.7 Herein we
present the first Good Manufacturing Practice (GMP) delivery
route toward MK-1029, which incorporates five unique
catalytic transformations, specifically (1) imine-Heck reaction
(palladium), (2) N−H insertion (iridium), (3) asymmetric
Special Issue: Excellence in Industrial Organic Syn-
thesis 2021
Received: April 14, 2021
https://doi.org/10.1021/acs.oprd.1c00128
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Scheme 1. Retrosynthesis of MK-1029 Featuring Opportunities for Catalysis
Scheme 2. (A) Representative Fischer Indole Synthesis; (B) Representative Imine-Heck Reaction
Scheme 3. Imine-Heck Reaction Used in the MK-1029 Synthesis
The former strategy was successfully applied to the synthesis of
MK-7246, initially through two independent steps (pyridazi-
none formation followed by cyclization to form the five-
membered ring with concomitant opening of the preliminary
heterocycle)11 and ultimately through a direct, single-step
ZnCl2-promoted process.5b In our synthesis, in the presence of
a wide range of Brønsted or Lewis acid promoters, aniline 9a
reacted smoothly with ketone 10 to form the corresponding
pyridazinone intermediate; however, completion of the Fischer
indole synthesis proceeded in poor yield (<30%) because of
the formation of a series of byproducts and required a
multistep purification of indole 8 to obtain sufficient quantities
to investigate the downstream chemistry. We hypothesized
that the presence of the electron-withdrawing fluorine atom
served to render the necessary [3,3]-sigmatropic shift less
favorable, opening up multiple undesired pathways.
reaction between electron-deficient and hindered 2-bromo-6-
fluoroaniline (9b) and diethyl oxopimelate (10) proceeded in
less than 20% conversion to imine 12. Unfortunately, the
acidic conditions required to effect the condensation are
incompatible with the basic conditions necessary for the Heck
reaction, meaning that we were unable to directly consume the
imine intermediately to help drive the equilibrium in the
forward direction. To enable this approach, we identified that
imine 12 could be generated in high yield from the acid-
catalyzed reaction between aniline 9b and diethyl ketal 13,
which was itself easily formed from ketone 10. By removal of
ethanol during this transformation, the resultant imine 12 was
poised to undergo the desired imine-Heck reaction without
workup or purification. Using high-throughput experimenta-
tion, we investigated a range of palladium-catalyzed conditions
for the Heck reaction. In these screening efforts, the use of
Pd(0) sources and tertiary amine bases provided the highest
conversion to indole. The presence of PtBu3 as the ligand, in
combination with Pd2(dba)3, led to >90% conversion to
product. Employing S-Phos or AmPhos afforded ∼80%
Because of the challenges associated with the Fischer indole
synthesis, it was critical to identify an alternative solution in the
form of the imine-Heck reaction (Scheme 3). In this approach,
formation of the imine proved to be extremely challenging; the
B
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Table 1. Optimization of N−H Insertion Conditions
a
entry
solvent for 15 (volumes )
solvent for Ir (volumes)
temperature (°C)
addition time (h)
assay yield (%)
1
2
3
4
5
6
7
8
9
DMF (3)
DMF (3)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMA (5)
DMF (5)
toluene (25)
toluene (30)
toluene (30)
toluene (30)
trifluorotoluene (30)
toluene (30)
toluene (30)
toluene (50)
toluene (50)
acetonitrile (50)
85
85
5
12
12
12
12
4
62
69
41
66
51
67
66
71
50 for 19 h, then 70 for 6 h
70
70
85
100
70
70
70
1
12
12
12
71
10
lactam 14
a
Volumes = mL of solvent/g of substrate.
Scheme 4. Generation of Ylide 15 and Catalytic N−H Insertion
conversion, while the use of all other phosphines afforded the
indole in <50% conversion. A range of solvents were effective
for this transformation, with cyclopentyl methyl ether (CPME)
and 2-methyltetrahydrofuran (MeTHF) providing the best
results. Ultimately, treatment of imine 12 with the combina-
tion of 2.5 mol % Pd2dba3, 10 mol % PtBu3·HBF4, and
dicyclohexylmethylamine (Cy2NMe)12 as the base in CPME as
the solvent at 100 °C afforded indole diester 8 in 84% yield
after crystallization across the two-step sequence.13 The
development of this first catalytic method set the stage for
the myriad contributions catalysis would make toward the
synthesis of MK-1029.
With the indole core in hand, we next investigated how to
prepare the tricycle. We leveraged the knowledge gained from
the MK-7246 process to make a rapid decision between two
possible approaches. In the first strategy, the indole was treated
with tert-butyl bromoacetate to form the corresponding
triester. A lack of selectivity for the desired ring closure was
observed in preliminary efforts to effect the necessary
Dieckmann cyclization en route to ketone 7. As a result,
efforts were focused on the second approach, which entailed an
iridium-catalyzed N−H insertion.5b,14 The necessary precursor
15 was prepared via base-mediated addition of trimethylsul-
foxonium iodide to diester 8. The selectivity for the ester
pendant to the 1-position of the indole is attributed to the
intermediacy of lactam 14, which can be independently
generated under the above reaction conditions in the absence
of the external nucleophile. Conditions for the catalytic ring
closure were investigated, with an emphasis on achieving the
highest yield while balancing the overall reaction volume and
starting material addition time, given that the carbene
precursor 15 would be added slowly to a dilute solution of
15
[Ir(COD)Cl]2 to avoid competing intermolecular pathways
(Table 1). N,N-Dimethylformamide (DMF) was identified as
the preferred solvent for dissolution of ylide 15 on the basis of
its superior solubility properties, and the use of toluene for the
Ir catalyst led to the highest yield of product ketone 7. While
more dilute conditions (entry 8) did lead to a slight increase in
assay yield (AY), it was determined that this benefit was offset
by the waste solvent generated and the need to remove that
quantity of toluene to carry out a high-yielding isolation.
Increasing the temperature led to a higher reaction rate (entry
3 vs entry 4 vs entry 6 vs entry 7), which enabled a
concomitant decrease in the addition time of ylide 15. The
conditions ultimately applied are those captured in entry 7, and
ketone 7 was obtained in 64% yield after crystallization. The
second catalytic sequence in the MK-1029 synthesis is shown
in Scheme 4.
Ketone 7 was next converted to chiral secondary alcohol 6.
Both Noyori transfer hydrogenation conditions and biocata-
lytic reduction using ketoreductases (KREDs) were inves-
tigated for this transformation. For the former, using 2 mol %
Ru(p-TsDENEB)Cl as the catalyst in dichloromethane
(DCM), the reaction proceeded to form alcohol 6 in
quantitative conversion with 93% ee. Unfortunately, prelimi-
nary efforts to upgrade to >99% ee as isolated mesylate 5 were
unsuccessful; a similar approach to upgrade azide 3 led to
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Scheme 5. Transformation of Ketone 7 into Azide 3 Driven by Biocatalytic Reduction
Scheme 6. Catalytic Generation of Terminal Alkyne 4a
Scheme 7. Ruthenium-Catalyzed AAC and Formation of MK-1029
isolation of essentially enantiopure material, but the recovery
was poor.
derivative followed by deprotection would provide the
requisite functionalized alkyne. At the same time, it was
recognized that the benzylic methylene protons of both 4a and
4b are highly acidified, and there exists a significant
thermodynamic driving force for the competitive formation
of allene 16 in either step and internal alkyne 17 upon
deprotection.19 As a result, modulation of the reaction pH was
critical to the success of both the Sonogashira coupling and
subsequent deprotection. Preliminary screening efforts for the
Sonogashira reaction employed acetone-protected acetylene
for this transformation. Unfortunately, even under mildly basic
conditions (e.g., using tertiary amine bases), the corresponding
allene was formed as the major product. When TMS-acetylene
was used as the coupling partner, >97% conversion to the
desired terminal alkyne 4b was observed in the presence of
Pd(OAc)2, an electron-rich phosphine ligand (t-Bu3P or t-
BuXPhos), and Cy2NMe as the base20 in methanol at 50 °C.
On scale, an 89% yield of TMS-alkyne 4b was obtained via this
catalytic manifold after distillation. Deprotection was then
conducted under buffered fluoride conditions (25 mol %
Me4NF·4H2O and 20% AcOH in DMF at 5 °C) to afford
terminal alkyne 4a, which was necessary for the final catalytic
reaction, in 90% yield (Scheme 6).
Having developed efficient catalytically driven routes to
azide 3 and terminal alkyne 4a, we were in position to
investigate the necessary azide−alkyne cycloaddition (AAC) to
form 1,5-disubstituted 1,2,3-triazole intermediate 2. This
transformation has been shown to proceed with the
appropriate regioselectivity under ruthenium-catalyzed con-
ditions.21 While this reaction and the corresponding triazole
products have seen considerable utility in medicinal chemistry,
especially in peptidomimetics, to the best of our knowledge,
the technology has not been applied to the larger-scale
synthesis of pharmaceutical drug candidates.22 Given this lack
of experience, we were delighted to find that adding azide 3 to
Given the short timelines for the project and the desire to
avoid DCM as a solvent, we shifted our attention to
implementing a biocatalytic reduction of ketone 7.16 The
primary challenge with the biocatalytic conditions was the
instability of the ketone toward the isopropanol/water solvent
mixture necessary for KRED hydrogen borrowing. Under the
initial loading conditions explored, the reaction required 3 days
to proceed to completion; for these conditions, only 78% of
ketone 7 remained in the absence of enzyme after 1 day, with a
multitude of small impurities observed by LC analysis. We
hypothesized that this degradation was due to susceptibility of
the indole ketone structure to enol/enamine formation and
oxidation pathways. Consistent with this theory, degassing the
reaction mixture improved the stability considerably, such that
93% ketone remained after 1 day. The resultant alcohol 6,
formed with >99% ee, was stable toward the reaction
conditions, also supporting the hypothesis of ketone instability.
Ultimately, the combination of degassing and running the
reaction under inert conditions with an increase in the enzyme
loading of Codexis P3H2 KRED to 12 wt % relative to the
starting material allowed the third catalytic reaction in the
sequence to achieve full conversion in 16 h in 98% assay yield.
The resulting isopropyl acetate solution of chiral alcohol 617
was treated with methanesulfonyl chloride and triethylamine to
afford mesylate 5 in 93% yield after crystallization. Subsequent
SN2 reaction of protected alcohol 5 with sodium azide in DMF
provided catalytic partner 3 in 89% yield (Scheme 5).
With azide 3 in hand, it was necessary to likewise prepare
alkyne 4a for use in the final catalytic step. We used an
additional catalytic transformation to access this alkyne, again
highlighting the criticality of catalysis to this overall process.
We envisioned that a Sonogashira coupling18 between p-
fluorobenzyl bromide (11) and a protected acetylene
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alkyne 4a in the presence of a catalytic quantity of
Cp*Ru(COD)Cl23 led to clean formation of the desired
triazole 2. The exact manner by which this reaction was carried
out was critical to the success of the transformation and also
ensured the safety of the practitioners given the high-energy
nature of both the azide starting material and the triazole
product. We observed that combining all of the reagents at
room temperature followed by heating led to a significant
exotherm and uncontrolled reflux of the toluene solution; this
outcome failed to align with our safety group’s recommenda-
tion to maintain the reaction temperature at 90 °C or below.
To offset this potential for exotherm, a toluene solution of the
Ru catalyst and alkyne 4a was heated to 70 °C, followed by
addition of a concentrated solution of azide 3, also dissolved in
toluene. The addition was conducted over 1 h, after which the
temperature was increased to 90 °C for 10 h. Through this
catalytic process, triazole 2 was obtained in 93% assay yield
(Scheme 7). The resultant toluene solution was taken directly
into the saponification. Hydrolysis of ethyl ester 2 was
achieved under basic conditions by addition of ethanol and
an aqueous solution of sodium hydroxide, affording MK-1029
(1) in 89% yield after crystallization.
In conclusion, we have developed a convergent route to the
CRTH2 antagonist MK-1029, which was used for multiple
GMP deliveries to fuel the early clinical development
program’s supply of API. Central to this synthesis was the
deployment of catalytic methods to enable the generation of
key intermediates in high yields and regio- and stereo-
selectivities. Specifically, after solving a difficult imine
formation, we developed a catalytic imine-Heck reaction to
install the key indole core 8.The indole was then converted to
the corresponding ketone 7 through the intermediacy of ylide
15 and its participation in an iridium-catalyzed N−H insertion
to form the third ring, likely proceeding through the
corresponding iridium carbene species. Biocatalysis, in the
form of a ketoreductase-promoted reduction, was responsible
for establishing the single stereocenter in MK-1029 with >99%
ee for alcohol 6. This fragment was subsequently transformed
to azide 3 via activation of the alcohol as the mesylate and
azide displacement. At the same time, alkyne 4a was obtained
through a two-step process that relied upon the use of a
Sonogashira coupling between p-fluorobenzyl bromide and
TMS-acetylene followed by deprotection; the optimized
conditions required precise tuning of the reaction pH to
balance high conversion in the Pd-catalyzed step given the
alkyne’s propensity to isomerize into conjugation with the aryl
ring. Azide 3 and alkyne 4a underwent ruthenium-catalyzed
AAC, the purported first of its kind on scale, to deliver the
penultimate 1,2,3-triazole 2 with the necessary 1,5-regiose-
lectivity. Saponification of the ethyl ester afforded MK-1029
(1) in high yield. The wide array of catalytic methods
enumerated here reflect the progress the field of organic
synthesis has made over the past 20 years in broadening the
toolbox of transformative methodologies, the criticality of
these reactions in industrial applications, and the perpetual
demand for innovation to enable complex molecule synthesis.
C18 column (50 mm × 3.0 mm, 2.7 μm) at 40 °C at a flow
rate of 1.5 mL/min at λ = 210 nm. Solution A was 0.05% TFA
in HPLC water, and solution B was 0.05% TFA in acetonitrile;
the gradient was 80% A, 20% B to 50% A, 50% B over 4 min,
5% A, 95% B over 1 min, hold for 1 min. The weight percent
was calculated via a sample of unknown purity standard
concentration HPLC peak area comparison against a pure
reference of known concentration.
1H NMR spectra were recorded on a 400 MHz Bruker
AVANCE NEO spectrometer. Chemical shifts are reported in
parts per million from tetramethylsilane with the solvent
resonance as the internal standard. Data are reported as
follows: chemical shift (multiplicity, coupling constant(s) in
hertz, integration). The following symbols were used for
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
br = broad, m = multiplet. 13C NMR spectra were recorded on
the same spectrometer at a frequency 100 MHz with uniform
proton decoupling. 19F NMR spectra were recorded on the
same spectrometer at a frequency of 376 MHz. HRMS data
were recorded on an Agilent Technologies 6230 LC/TOF
instrument. Melting point data were acquired on a Tianjin
Analytical Instrument RY-2 melting point monitor. Optical
rotation data were acquired on a Puldolph Autopol III
instrument.
Heptanedioic Acid, 4,4-Diethoxy-, 1,7-Diethyl Ester
(13) [14160-68-0]. To a 1 L round-bottom flask outfitted
with nitrogen inlet, overhead stirrer, and reflux condenser were
charged EtOH (235 mL), triethyl orthoformate (78 mL, 469
mmol), and diethyl 4-oxopimelate (50 mL, 235 mmol). p-
Toluenesulfonic acid monohydrate (0.446 g, 2.34 mmol) was
added, and the reaction mixture was heated to reflux for 18 h.
1
The reaction mixture was sampled and analyzed by H NMR
spectroscopy. The spectrum showed an 11:1 diethyl
ketal:ketone molar ratio, reflecting 92% conversion. Volatiles
(∼250 mL) were removed by distillation under vacuum. The
remaining orange ketal solution was dissolved in toluene (270
mL) and washed with 2.5% NaHCO3(aq) (216 mL). The
toluene layer was washed with water (162 mL). Toluene was
removed under vacuum, and diethyl ketal 13 (76.4 g at 90 wt
% purity, 226 mmol, 96% yield) was isolated as a yellow oil and
used as-is in the subsequent step.
Imine 12. 2-Bromo-6-fluoroaniline (16.97 mL, 150 mmol),
diethyl ketal (55.8 g, 165 mmol) 13, and acetic acid (1.717
mL, 30.0 mmol) were combined in a 250 mL three-neck
round-bottom flask equipped with a distillation head under
nitrogen. The reaction mixture was heated to react and distill
off ethanol, settling at an internal temperature of 123 °C that
then increased to 145 °C. Once the distillation had stopped,
the remaining solution was assayed by 1H NMR spectroscopy,
which revealed >98% conversion to imine 12. The reaction
mixture was allowed to cool to room temperature for use in the
subsequent Heck reaction.
1H-Indole-2-propanoic Acid, 3-(2-Ethoxy-2-oxoeth-
yl)-7-fluoro, Ethyl Ester (8) [1242272-98-5]. To a 250
mL three-neck round-bottom flask equipped with a condenser
were added Pd2dba3 (1.707 g, 1.864 mmol) and tri-tert-
butylphosphonium tetrafluoroborate (2.164 g, 7.46 mmol) in
CPME (102 mL, 876 mmol) under nitrogen. Degassed N-
methyldicyclohexylamine (7.91 mL, 37.3 mmol) was added,
and the mixture was further degassed for 30 min. In a separate
250 mL round-bottom flask under nitrogen, imine 12 (30.0 g,
74.6 mmol) was dissolved in CPME (102 mL, 876 mmol). N-
Methyldicyclohexylamine (23.73 mL, 112 mmol) was added,
EXPERIMENTAL SECTION
■
General. All of the reagents were used without further
purification. Products were authenticated against commercially
available or previously described reagents.6a,c,24 LCMS data
were acquired on an Agilent 1260 Infinity liquid chromatog-
raphy system and quadrupole MS with an Ascentis Express
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and the mixture was degassed for 30 min. The imine solution
was transferred to the catalyst solution by vacuum, and the full
reaction mixture was degassed for an additional 10 min and
then heated to reflux for 16 h. The reaction mixture was cooled
to room temperature and washed with 2 N HCl (2 × 60 mL),
5% NaHCO3(aq) (1 × 60 mL), and water (1 × 40 mL).
CPME was distilled under vacuum and replaced with toluene
(40 mL) to enable further CPME removal. Heptane (60 mL)
was added at ∼40 °C, and crystallization was observed. The
heterogeneous solution was cooled to −20 °C and stirred
overnight. Indole 8 (21.8 g, 67.7 mmol, 91% yield) was
isolated by filtration and subsequent cold heptane wash.
Sulfoxonium, [4-[3-(2-Ethoxy-2-oxoethyl)-7-fluoro-
1H-indol-2-yl]-2-oxobutyl]dimethyl-, Inner Salt (15).
KOtBu (1 M) in THF (180 mL) was charged to a 500 mL
round-bottom flask under nitrogen. Me3SOI (43.3 g, 197
mmol) was charged portionwise at room temperature. The
resulting suspension was heated to 66 °C for 2 h. After the
reaction mixture was cooled to 30 °C, a solution of indole 8
(19.8 g, 61.0 mmol) in THF (40 mL) was charged over 10
min. The reaction mixture was heated to 60 °C for 2.5 h and
then cooled to room temperature. Water (300 mL) and EtOAc
(300 mL) were charged, and the temperature rose from 20.1 to
23.5 °C. The layers were separated, and the aqueous layer was
back-extracted with EtOAc (2 × 200 mL). The combined
organic layers were washed with saturated NaHCO3 (500 mL).
The organic layer was further washed with 2 wt % NaCl(aq)
(200 mL). The organic layer was concentrated and flushed
with EtOAc under reduced pressure to a target volume of ∼20
mL of EtOAc. Heptane (80 mL) was charged over 30 min, and
crystallization was observed. The suspension was filtered, and
the filter cake was washed with 25% EtOAc/heptane (25 mL)
and then dried at room temperature under vacuum and
nitrogen to provide ketosulfoxide 15 as an off-white solid
(16.72 g, 94 wt %, 70.1% corrected yield). Melting point: 142
°C. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H), 7.21 (d,
J = 7.8 Hz, 1H), 6.91 (td, J = 7.8, 4.9 Hz, 1H), 6.83 (ddd, J =
11.4, 7.8, 0.9 Hz, 1H), 4.79 (s, 1H), 4.05 (q, J = 7.1 Hz, 2H),
3.77−3.66 (m, 2H), 3.44 (s, 6H), 2.97−2.85 (m, 2H), 2.47−
2.36 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 187.86, 171.90, 150,40, 147.99, 139.35, 132.58,
123.25, 119.17, 114.47, 105.82, 104.80, 73.01, 60.57, 40.89,
40.46, 30.19, 22.35, 14.59. 19F NMR (376 MHz, DMSO-d6): δ
−134.08, −134.32, −134.73. HRMS [M + H]+
(C18H23FNO4S) m/z: calcd 368.1322, obs 368.1349.
Pyrido[1,2-a]indole-10-acetic Acid, 4-Fluoro-6,7,8,9-
tetrahydro-7-oxo-, Ethyl Ester (7) [1242273-00-2].
Toluene (900 mL) was charged to a 3 L three-neck round-
bottom flask, and the solution was sparged with nitrogen for 20
min. [Ir(COD)Cl]2 (769.4 mg, 1.145 mmol) was charged.
After sparging with nitrogen for an additional 20 min, the
solution was heated to 100 °C. Ketosulfoxide 15 (30.03 g, 76
mmol) was dissolved in DMF (120 mL) in a 250 mL round-
bottom flask. The resulting solution was sparged with nitrogen
for 15 min and then transferred to the catalyst solution at 100
°C over 1 h, with a color change from red to yellow, and the
mixture was allowed to stir for an additional 20 min and then
cooled to room temperature, The reaction mixture was washed
with water (2 × 300 mL), and an LC assay of the organic
phase showed 15.64 g of product (AY = 71%). Silica gel (60.80
g, 230−400 mesh, grade 60) was charged to the organic phase,
and the mixture was stirred overnight. The suspension was
filtered, and the silica gel was washed with additional toluene
(3 × 300 mL). The filtrates were combined, and the toluene
was concentrated in vacuo. Isopropyl alcohol (IPA) was
charged to azeotrope the remaining toluene. Water (120 mL)
was added to the IPA solution over 15 min, and the product
crystallized. The slurry was stirred for 3 h and then filtered, and
the cake was washed with 1:2 water:IPA (75 mL) and dried
under nitrogen and vacuum. Ketone 7 was isolated as a peach-
colored solid (14.9 g, 95 wt %, 64% yield).
(7S)-Pyrido[1,2-a]indole-10-acetic Acid, 4-Fluoro-
6,7,8,9-tetrahydro-7-hydroxy-, Ethyl Ester (6). To a 250
mL round-bottom flask with overhead stirring, temperature
control, a condenser, and a nitrogen line was added 0.1 M pH
7.0 K2HPO4 buffer (108 mL). The buffer was degassed with
nitrogen for 1 h. NADP (133 mg) and CDX KRED P3H2
(600 mg, 12 wt %) were dissolved in the pH 7.0 buffer. IPA
(14.5 L) was added to a separate 250 L round-bottom flask
and degassed with nitrogen for 1 h. Ketone 7 (5.0 g, 16.25
mmol) was added to the degassed IPA, and the solution was
warmed to 45 °C. The warm solution was added to the enzyme
solution, resulting in the formation of an orange-brown
heterogeneous mixture at 29 °C. The reaction mixture was
heated to 33−35 °C and aged overnight. After 20 h, isopropyl
acetate (IPAc) (100 mL) was added. The aqueous layer was
removed, leaving the organic rag layers. The combined organic
and emulsified rag layers were filtered through a bed of Solka-
Floc with additional IPAc (30 mL). The IPAc layer was
washed with 1% brine (50 mL) and water (50 mL). An assay
of the organic layer found 4.97 g of alcohol 6 (105% AY, >99%
ee). The IPAc solution was used as-is in the next step with
additional flushing. For characterization purposes, the solution
1
was concentrated to a yellow oil. [α]2D1 +4.82 (MeOH). H
NMR (400 MHz, DMSO-d6): δ 7.23 (d, J = 7.9 Hz, 1H), 6.93
(td, J = 7.8, 4.7 Hz, 1H), 6.83 (ddd, J = 12.9, 7.8, 0.9 Hz, 1H),
5.24 (d, J = 3.5 Hz, 1H), 4.38 (ddd, J = 12.0, 4.0, 1.7 Hz, 1H),
4.22 (hept, J = 3.6 Hz, 1H), 4.13 (ddd, J = 12.2, 5.3, 2.2 Hz,
1H), 4.05 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 2.99 (ddd, J =
16.6, 8.5, 5.8 Hz, 1H), 2.81 (dt, J = 16.7, 6.1 Hz, 1H), 2.02−
1.78 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 171.21, 151.11, 148.71, 135.87, 132.19, 123.26,
119.65, 114.31, 106.23, 103.43, 63.44, 60.40, 51.89, 29.94,
27.69, 21.22, 18.28, 14.57. 19F NMR (376 MHz, DMSO-d6): δ
−136.30, −136.54, −136.59, −136.93, −136.94. HRMS [M +
H]+ (C16H18FNO3) m/z: calcd 292.1343, obs 292.1338.
(7S)-Pyrido[1,2-a]indole-10-acetic Acid, 4-Fluoro-
6,7,8,9-tetrahydro-7-[(methylsulfonyl)oxy-], Ethyl Ester
(5) [1242273-04-6]. To a 250 mL round-bottom flask
equipped with an overhead stirrer, an addition funnel, and a
temperature probe was charged a 15.5 wt % solution of alcohol
6 (42.90 g, 22.83 mmol) in IPAc from the previous step. The
reaction mixture was cooled to −20 °C. Et3N (6.5 mL, 46.6
mmol) was added in one portion, and the internal temperature
was allowed to equilibrate to −10 °C. MsCl (2.80 mL, 35.9
mmol) was added to the reaction mixture using an addition
funnel over a period of 90 min; the internal temperature was
maintained below 10 °C. The reaction mixture was stirred for
an additional 15 min and then cooled to −2 °C, and a solution
of 1 N HCl (32 mL) was added over 20 min via an addition
funnel. The layers were separated, and the organic layer was
washed with 5% NaHCO3(aq) (32 mL) and 0.5% NaCl(aq)
(32 mL). The solution was concentrated and azeotropically
dried with additional IPAc. The resultant solution was
crystallized by slow addition of heptane (75 mL). The
suspension was filtered, and the crystals were washed with
F
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9:1 heptane/IPAc and dried overnight under vacuum and
nitrogen. Mesylate 6 was isolated as a light-yellow crystalline
solid (8.05 g, 95% yield, 93% yield over two steps). Melting
(3.99 g, 23.81 mmol) was added portionwise over 15 min.
Toluene (25 mL) was added at the end of the reaction,
followed by slow addition of 1 N HCl (50 mL). The reaction
mixture was stirred and allowed to warm to room temperature
over 30 min. The aqueous phase was removed, and the organic
phase was washed with 1% NaHCO3(aq) (50 mL) and H2O
(50 mL) and then dried over Na2SO4 (5.50 g). The suspension
was filtered, and the solids were washed with minimal toluene.
The terminal alkyne was stored as a light-yellow 18.7 wt %
solution in toluene (6.62 g, 96% yield).
1
point: 57 °C. [α]2D1 +26.08 (MeOH). H NMR (400 MHz,
DMSO-d6): δ 7.28 (d, J = 7.8 Hz, 1H), 6.98 (td, J = 7.9, 4.7
Hz, 1H), 6.89 (ddd, J = 12.8, 7.9, 0.9 Hz, 1H), 5.41 (h, J = 2.9
Hz, 1H), 4.67−4.50 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.78−
3.63 (m, 2H), 3.34 (s, 3H), 3.09−2.88 (m, 2H), 2.29 (dd, J =
13.4, 4.8 Hz, 1H), 2.11 (tdd, J = 13.5, 6.2, 2.0 Hz, 1H), 1.18 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 171.50,
151.05, 148.65, 134.72, 132.10, 123.26, 120.12, 114.66, 106.65,
104.24, 74.90, 60.65, 49.52, 37.44, 29.83, 25.09, 17.18, 14.57.
19F NMR (376 MHz, DMSO-d6): δ −136.33, −136.92. HRMS
[M + H]+ (C17H20FNO5S) m/z: calcd 370.1119, obs
370.1110.
(7R)-Pyrido[1,2-a]indole-10-acetic Acid, 4-Fluoro-7-
[5-[(4-fluorophenyl)methyl]-1H-1,2,3-triazol-1-yl]-
6,7,8,9-tetrahydro-, Ethyl Ester (2). To a 250 mL round-
bottom flask under nitrogen were added an 18.7 wt % solution
of alkyne 4a in toluene (37.4 g, 52.2 mol) and Cp*Ru(COD)
Cl (324 mg, 0.854 mmol). The solution was degassed for 30
min. An addition funnel containing azide 3 (15.0 g, 47.4
mmol) dissolved in toluene (13.1 mL) was attached. The
reaction mixture was heated to 70 °C, at which point the azide
solution was added to the reaction mixture over 50 min.26 The
temperature was maintained at 70 °C for 10 min after the
addition and then increased to 90 °C over 15 min. The
temperature was maintained at 90 °C for 12 h, and then the
mixture was cooled to room temperature. Darco KB-G (4.8 g,
25 wt %) was added, and the suspension was stirred for 90
min. The mixture was filtered through Solka-Floc, washing
with toluene. The combined filtrates were concentrated to
obtain a 22 wt % solution of triazole 2 in toluene (19.86 g, 93%
AY). A sample was concentrated to a brown foam for
characterization. [α]D21 +45.64 (MeOH). 1H NMR (400 MHz,
DMSO-d6): δ 7.56 (s, 1H), 7.38−7.31 (m, 2H), 7.27 (d, J =
7.9 Hz, 1H), 7.23−7.15 (m, 2H), 6.97 (td, J = 7.9, 4.6 Hz,
1H), 6.86 (ddd, J = 12.8, 7.9, 0.9 Hz, 1H), 5.17 (qd, J = 9.1,
7.2, 3.1 Hz, 1H), 4.70−4.56 (m, 1H), 4.47 (dd, J = 11.7, 8.9
Hz, 1H), 4.26 (s, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.69 (d, J = 3.6
Hz, 2H), 3.06 (dt, J = 16.8, 4.9 Hz, 1H), 2.89 (ddd, J = 16.6,
10.6, 5.7 Hz, 1H), 2.38−2.18 (m, 1H), 2.17−2.03 (m, 1H),
1.18 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ
171.49, 162.84, 160.43, 151.06, 148.65, 137.35, 135.00, 133.90,
133.02, 132.26, 130.97, 123.10, 120.11, 115.98, 114.55, 106.71,
104.22, 60.43, 52.50, 48.92, 29.95, 27.57, 26.92, 20.80, 14.58.
19F NMR (376 MHz, DMSO-d6): δ −115.93, −136.55. HRMS
[M + H]+ (C25H24F2N4O2) m/z: calcd 451.1940, obs
451.1944.
MK-1029 (1). Triazole 2 (45.15 g, 28.1 mmol) was charged
as a 28 wt % solution in toluene to a 250 mL round-bottom
flask. EtOH (33.9 mL) was added, and the mixture was
degassed for 15 min. A 5 M NaOH(aq) solution (6.23 mL,
31.2 mmol) was added via an addition funnel over 10 min. The
reaction mixture was heated to 50 °C for 2.5 h and then cooled
to room temperature, and 1:1 EtOH/H2O (50 mL) was added.
The layers were separated, and the aqueous layer was stirred
over Ecosorb C-908 (4.6 g, 40 wt % based on theoretical yield)
for 75 min. The suspension was filtered through Solka-Floc,
washing with 1:1 EtOH/H2O (20 mL) and 1:2 EtOH/H2O
(20 mL). The combined filtrates (16.4 kg) were charged to a
clean 250 mL round-bottom flask. The mixture was diluted
with THF (15 mL) and stirred under nitrogen. Hydrochloric
acid (2.69 mL) was added via syringe, leading to
crystallization. The slurry was filtered, and the cake was
washed with 5:4:2 H2O/EtOH/THF, 2:1:1 H2O/EtOH/THF,
and water. The solid was dried under nitrogen and vacuum.
MK-1029 (10.55 g, 25.0 mmol, 89% yield) was isolated as an
(7R)-Pyrido[1,2-a]indole-10-acetic Acid, 7-Azido-4-
fluoro-6,7,8,9-tetrahydro-, Ethyl Ester (3). To a 100 L
round-bottom flask equipped with an overhead stirrer,
temperature probe, and reflux condenser were sequentially
charged mesylate 6 (10.38 g, 95.5 wt %, 26.8 mmol), DMF
(51.9 mL), NaN3 (2.84 g, 43.7 mmol), and Et3N (0.4 mL, 2.87
mmol) under a constant stream of N2. The reaction vessel was
heated to 70 °C for 18 h. The mixture was cooled to room
temperature, and water (62 mL) was slowly added with
vigorous stirring. The reaction mixture was filtered, and the
crystals were washed with 1:1 DMF/water, 3:7 DMF/water,
and water (14 L). The brown solid was dried under vacuum
and nitrogen to give 3 (7.47 g, 88% yield). Melting point: 55
°C. [α]1D9 −19.39 (MeOH). 1H NMR (400 MHz, DMSO-d6):
δ 7.26 (dd, J = 7.8, 1.0 Hz, 1H), 6.97 (td, J = 7.8, 4.7 Hz, 1H),
6.87 (ddd, J = 12.8, 7.9, 1.0 Hz, 1H), 4.54−4.41 (m, 2H),
4.35−4.22 (m, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.67 (s, 2H),
2.94 (td, J = 6.3, 2.6 Hz, 2H), 2.19−1.97 (m, 2H), 1.17 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 171.49,
151.05, 148.65, 134.96, 132.15, 123.25, 120.04, 114.49, 106.71,
106.54,104.21, 60.62, 55.18, 48.49, 29.84, 24.50, 18.47, 14.58.
19F NMR (376 MHz, DMSO-d6): δ −136.27. HRMS [M +
H]+ (C16H17FN4O2) m/z: calcd 317.1408, obs 317.1408.
4-Fluoro-1-[3-(trimethylsilyl)prop-2-yn-1-yl]benzene
(4b) [133218-06-1]. To a 250 mL three-neck round-bottom
flask equipped with a condenser and dried overnight under
nitrogen were added methanol (105 mL), tri-tert-butylphos-
phonium tetrafluoroborate (460 mg, 0.159 mmol), palladium-
(II) acetate (0.178 g, 0.794 mmol), and N-methyldicyclohexyl-
amine (29.5 g, 151 mmol). The reaction mixture was degassed
for 45 min under nitrogen. 4-Fluorobenzyl bromide (9.89 mL,
79 mmol) and trimethylsilylacetylene (12.09 mL, 87 mmol)
were added. The reaction mixture was heated to 50 °C for 90
min and then cooled to room temperature. Heptane (75 mL)
was added to the reaction mixture, followed by slow addition
of 1 N HCl (60 mL). The resulting mixture was cooled with an
ice−water bath, and the temperature was allowed to increase to
a maximum of 25 °C. The layers were separated, and the
organic layer was washed with water (60 mL). Heptane was
removed by rotary evaporation. Vacuum distillation at 112−
118 °C and 10 Torr25 afforded TMS-alkyne 4b (14.57 g, 89%
yield) as an oil that was stored in the freezer to prevent
decomposition.
1-Fluoro-4-(prop-2-yn-1-yl)benzene (4a) [70090-68-
5]. A 250 mL round-bottom flask was charged with a solution
of TMS-alkyne 4b (12.78 g, 83 wt %, 51.4 mmol) in DMF
(51.1 mL). The reaction mixture was cooled to 0 °C, and
acetic acid (0.6 mL, 10.48 mmol) was added. Me4NF·4H2O
G
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off-white crystalline solid. Melting point: 96 °C. [α]2D1 +51.95
methyltetrahydrofuran, (MeTHF); dba, dibenzylideneacetone;
Cy2NMe, dicyclohexylmethylamine; COD, cyclooctadiene;
DMF, N,N-dimethylformamide; p-TsDENEB, N-[2-[2-(4-
methylbenzyloxy)ethyl]amino-1,2-diphenylethyl]-p-toluenesul-
fonamide]; DCM, dichloromethane; KRED, ketoreductase;
AAC, azide−alkyne cycloaddition; API, active pharmaceutical
ingredient
1
(MeOH). H NMR (400 MHz, DMSO-d6): δ 7.57 (s, 1H),
7.43−7.22 (m, 3H), 7.22−7.09 (m, 2H), 6.95 (td, J = 7.8, 4.5
Hz, 1H), 6.83 (dd, J = 12.8, 7.8 Hz, 1H), 5.12 (d, J = 8.4 Hz,
1H), 4.53 (d, J = 11.8 Hz, 1H), 4.47−4.31 (m, 1H), 4.24 (s,
2H), 3.54 (t, J = 4.6 Hz, 2H), 3.05 (dt, J = 16.8, 4.9 Hz, 1H),
2.89 (ddd, J = 16.6, 10.6, 5.7 Hz, 1H), 2.37−2.18 (m, 1H),
2.12−2.01 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ
174.89, 162.84, 160.42, 150.99, 148.59, 137.34, 133.89, 132.94,
130.99, 123.01, 122.92, 119.57, 119.51, 116.10, 115.89, 115.08,
115.05, 107.77, 106.24, 52.79, 48.96, 32.77, 27.55, 27.28,
20.66. 19F NMR (376 MHz, DMSO-d6): δ −115.91, −137.02.
HRMS [M + H]+ (C23H20F2N4O2) m/z: calcd 451.1940, obs
451.1944.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00128.
■
sı
MK-1029 characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Rebecca T. Ruck − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States; orcid.org/0000-0001-9980-9675;
Email: Rebecca_ruck@merck.com
Authors
Jun Pan − Process Research & Development, MRL, Merck &
Co., Inc., Rahway, New Jersey 07065, United States; Present
Address: J.P.: Incyte Therapeutics, Wilmington, DE
19803, United States.
Rishi G. Vaswani − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States; Present Address: R.G.V.: Foghorn Therapeutics,
Cambridge, MA 02139, United States.
Birgit Kosjek − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States
Neil A. Strotman − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States; orcid.org/0000-0002-5350-8735
Chaoxian Cai − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States
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Guy R. Humphrey − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States; orcid.org/0000-0001-8634-1567
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https://pubs.acs.org/10.1021/acs.oprd.1c00128
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Chunrui Sun, Zhiguo (Jake) Song, and
Pharmaron for help with compound characterization.
■
ABBREVIATIONS
CRTH2, chemo-attractant receptor expressed on Th2 cells;
PGD2, prostaglandin d2; CPME, cyclopentyl methyl ether; 2-
■
Castan
̃
ón, J.; Cherney, A. H.; Christensen, M.; Damon, D. B.;
H
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corresponding HBr salt exhibited better physical properties in the
nonpolar solvents used.
(13) Pd(0) and Pd(II) sources were investigated for the indole-Heck
reaction, but reduction to Pd(0) in the case of Pd(II) catalysts failed
to afford appreciable quantities of product.
(14) Mangion, I. K.; Nwamba, I. K.; Shevlin, M.; Huffman, M. A.
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(15) [Ir(COD)2]BF4 was also investigated as a catalyst, but the
conversion was significantly lower.
(16) Moody, T. S.; Mix, S.; Brown, G.; Beecher, D. Ketone and
aldehyde reduction. In Science of Synthesis: Biocatalysis in Organic
Synthesis; Faber, K., Fessner, W.-D., Turner, N. J., Eds.; Thieme:
Stuttgart, Germany, 2015; p 421.
(17) Isopropanol was rigorously removed during workup and
azeotropic drying to avoid the formation of isopropyl mesylate in the
next step, which could go on to form isopropyl azide.
(18) Chinchilla, R.; Nájera, C. The Sonogashira Reaction: A
Booming Methodology in Synthetic Organic Chemistry. Chem. Rev.
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(19) Structures of 4, 16, and 17:
.
(20) Use of Cs2CO3 as the base led to near-exclusive formation of
the corresponding allene.
(21) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. Ruthenium-Catalyzed
Cycloaddition of Alkynes and Organic Azides. J. Am. Chem. Soc.
2005, 127, 15998−15999. (b) Rasmussen, L. K.; Boren, B. C.; Fokin,
V. V. Ruthenium-Catalyzed Cycloaddition of Aryl Azides and
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S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V.
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Mechanism. J. Am. Chem. Soc. 2008, 130, 8923−8930.
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(22) Johansson, J. R.; Beke-Somfai, T.; Said Stalsmeden, A.; Kann,
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX