Bio- And Chemocatalysis for the Synthesis of Late Stage SAR-Enabling Intermediates for ROMK Inhibitors and MK-7145 for the Treatment of Hypertension and Heart Failure

Article abstract of DOI:10.1021/acs.oprd.0c00314

A synthetic strategy to provide two late-stage intermediates for the synthesis of diverse analogues of ROMK inhibitors for the treatment of hypertension and heart failure is described. Key transformations include carbonylation of a bromoarene, regioselect

Full text of DOI:10.1021/acs.oprd.0c00314

pubs.acs.org/OPRD
Article
Bio- and Chemocatalysis for the Synthesis of Late Stage SAR-
Enabling Intermediates for ROMK Inhibitors and MK-7145 for the
Treatment of Hypertension and Heart Failure
Rebecca T. Ruck,* Qinghao Chen, Nelo Rivera, Jongrock Kong, Ian K. Mangion, Lushi Tan,
and Fred J. Fleitz
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ABSTRACT: A synthetic strategy to provide two late-stage intermediates for the synthesis of diverse analogues of ROMK inhibitors
for the treatment of hypertension and heart failure is described. Key transformations include carbonylation of a bromoarene,
regioselective vinyl ether Heck coupling and bromination, and asymmetric enzyme-mediated ketone reduction and epoxide ring
closure. On selection of MK-7145 (1) as clinical candidate, conditions were developed to convert 2 equiv of the epoxide
intermediates to the C -symmetric active pharmaceutical ingredient.
2
KEYWORDS: carbonylation, Heck, ketoreductase, epoxide
he renal outer medullary potassium channel (ROMK)
the kilogram-scale synthesis of an identified clinical candidate.
Herein, we present the synthesis of α-bromoketone 3 and
styrene oxide 4 as late-stage SAR-enabling intermediates and
direct translation of this strategy to the multikilogram scale
T
was recently reported as a potential target for the
1
treatment of hypertension and heart failure. As a result, a drug
discovery program was established to pursue the synthesis and
evaluation of a series of oral small molecule ROMK inhibitors
preparation and rapid progression of C -symmetric clinical
2
2
3b
that would function as diuretics. Additional development
candidate, MK-7145 (1, Figure 1c).
identified the β-dialkylaminoalcohol framework 2 (Figure 1a)
We envisioned that styrene oxide 4 would be directly
accessible from bromoketone 3 via enzymatic reduction and
cyclization of the resulting bromohydrin to the corresponding
epoxide. As a result, we initially targeted an efficient synthesis
of compound 3 as the key intermediate in this SAR-enabling
strategy. Given the ultimate goal of translating this chemistry
to the multikilogram scale, additional requirements included
the use of readily available, inexpensive starting materials,
minimization of the number of steps, and scalability of all
transformations. To that end, we identified 3-hydroxy-2-
methylbenzoic acid (5), known to be widely available on
scale for $80/kilogram, as an ideal starting material for this
synthetic sequence. Our proposed retrosynthesis is shown in
Scheme 1.
In a forward sense, the first two steps of the synthetic
sequence involved classical organic chemistry reactions
Figure 1. (a) Key pharmacophore; (b) Synthetic intermediates for
ROMK program; (c) MK-7145.
(
Scheme 2). Benzoic acid 5 underwent smooth reduction
4
with in situ generated borane in tetrahydrofuran to afford
benzyl alcohol 6. Careful control of the stoichiometry of
sodium borohydride and boron trifluoride diethyl etherate, as
well as aqueous workup to remove borate salts before product
as critical to improved hERG (human Ether-a-go-go-Related
̀
3
Gene) selectivity and improved pharmacokinetic profile. An
efficient synthesis of late-stage intermediates 3 and 4 was
critical for rapid interrogation of this series of novel ROMK
inhibitors (Figure 1b). From bromoketone 3, β-aminoalcohol
analogues could be accessed through a two-step sequence
Special Issue: Celebrating Women in Process Chem-
istry
involving S 2 displacement with an amine followed by
N
reduction; similarly, direct epoxide opening of styrene oxide
Received: July 2, 2020
4
would provide a complementary approach depending on the
identity of the amine nucleophile. We envisioned that the ideal
approach to these intermediates would be directly applicable to
©
XXXX American Chemical Society
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX
A

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Scheme 1. Retrosynthesis for Synthetic Intermediates 3 and
4
regioselectivity of the subsequent Heck reaction. Most aryl
sulfonates (-Ms, -Ts, -4-NO C H , -2,4-di-NO C H ) pro-
2
6
4
2
6
3
vided low conversions to product, with regioselectivities
ranging from 1:1 to 2:1 in favor of the desired α-branched
vinyl ether over its terminal regioisomer. On switching to the
1
0
aryl triflate 13,
we observed high conversion and
regioselectivity in the Heck reaction to the desired product
as a result of the triflate favoring an electronically controlled
10c
cationic Heck oxidative addition Pd complex mechanism.
The crude reaction stream was used directly in the
bromination, affording bromoketone 3 in 72% yield over the
three-step sequence. Ultimately, we successfully developed a
six-step, 45% yielding sequence from a readily available
commercial starting material to provide the first of two
valuable late-stage synthetic intermediates for further elabo-
ration to ROMK inhibitors.
isolation, allowed for isolation of the desired product in 93%
yield. Bromination of benzyl alcohol 6 was carried out with N-
bromosuccinimide (NBS) in a mixture of trifluoroacetic acid
and acetonitrile to afford p-bromophenol 7. The yield of this
transformation proved highly temperature-dependent. At −30
°C, o-bromophenol regioisomer 8 (9%), dibromide 9 (3%),
and TFA ester 10 (5%) impurities were observed, and desired
bromophenol 7 was isolated in only 74% yield. Formation of
these impurities was suppressed at −45 °C, and a 10% increase
The second intermediate of interest was styrene oxide 4. We
quickly demonstrated that sodium borohydride reduction and
treatment with base provided racemic access to this
compound. Nonetheless, with the desired epoxide enantiomer
defined, we sought to develop an asymmetric reduction of
bromoketone 3 to insert into this sequence and focused our
5
in isolated yield to 84% was obtained.
With bromoarene 7 in hand, we sought next to form the
lactone moiety present in both desired intermediates. We
envisioned two approaches for installation of the requisite
carbon. Initial efforts centered on cyanation of the arene with
11
efforts on the use of a ketoreductase enzyme. We rapidly
6
identified commercial Codexis KRED MIF-20 as providing
smooth reduction of the bromoketone to the corresponding
bromohydrin in >99% ee. After conclusion of the enzymatic
reaction, K CO was added to effect cyclization to the epoxide
copper(I) cyanide (CuCN). This transformation proceeded
via the cyano intermediate 11 at 145 °C. Continued heating at
9
1
5 °C, with addition of 5.0 equiv of water, afforded the lactone
2 after 20 h (Scheme 3a). Unfortunately, while the reaction
2
3
4
.
profile under these conditions appeared very clean, the isolated
yield was only 62%. We attributed this result to entrainment of
the product in the solids that formed during the reaction.
Additionally, an excess of CuCN was required to achieve high
conversion, which was undesirable for future large-scale
syntheses. As a result, we turned our attention to palladium-
With these syntheses in hand, tens of grams of each of
bromoketone 3 and epoxide 4 were then available to the
medicinal chemistry team to react with amines to prepare the
corresponding β-aminoalcohols. In turn, the team evaluated
the potency, physical properties, and toxicities of a wide variety
of structural analogues and identified MK-7145 (1) as its
clinical candidate possessing the desired balance of these
7
catalyzed carbonylation to form the requisite lactone. At high
pressure (85−90 psi CO) and temperature (130 °C), in the
presence of 2.0 mol % Pd(OAc)2 and 2.4 mol %
diphenylphosphinopropane (dppp), bromoarene starting ma-
3
features. Our defined strategy to develop an efficient, scalable
synthesis of epoxide 4 proved beneficial for the large-scale
preparation of MK-7145. In particular, we envisioned that
treatment of 2 equiv of the epoxide with 1 equiv of piperazine
terial 7 underwent clean carbonylation to form lactone 12 in
8
8
0% isolated yield (Scheme 3b). These arene core
12
would provide direct access to the desired compound. We
examined a series of solvents at elevated temperatures for the
bis-epoxide opening. While running the reaction in tert-amyl
alcohol provided the appropriate polarity to enable the fastest
rate, the best ratio of the desired product observed relative to
its monoterminal epoxide opening, mono-internal opening
regioisomer 14 was only 2:1. Changing to N,N-dimethylace-
tamide (DMAc) as solvent led to similar mixtures at higher
manipulations collectively positioned the synthesis for
subsequent modification of the substrate to install the
necessary bromoketone and epoxide functionalities.
In order to transform the phenol 12 to the desired
bromoketone 3, a sequence of phenol activation, regioselective
9
Heck reaction with n-butyl vinyl ether, and treatment of the
resultant vinyl ether with NBS was designed (Scheme 4). We
prepared a series of aryl sulfonates in an effort to assess the
Scheme 2. Preparation of Bromophenol 7
B
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Scheme 3. Lactone 12 Formation: (a) CuCN Conditions; (b) Carbonylation Conditions
Scheme 4. Conversion to Desired Synthetic Intermediates 3 and 4
Scheme 5. End-Game for MK-7145
temperatures. The best ratio (close to 5:1) was observed in
toluene, but the rate of reaction was severely compromised,
and the monoepoxide opening 15 was the major product.
Ultimately, use of a 1:1 mixture of toluene and DMAc at 140
We have described a strategy that has enabled the rapid
preparation of a variety of structural analogues for inter-
rogation by our ROMK discovery team and subsequent large-
scale synthesis of a clinical candidate. Specifically, intermedi-
ates 3 and 4 were prepared via 6- and 7-step sequences,
respectively. Key transformations along the route included a
palladium-catalyzed carbonylation of a bromoarene, a highly
regioselective enol ether Heck reaction between an aryl triflate
and n-butyl vinyl ether, followed by NBS treatment to afford
the corresponding bromoketone, and highly enantioselective
ketoreductase-mediated reduction of the bromoketone and
subsequent cyclization to form the desired epoxide. Reaction
of 2 equiv of the epoxide intermediate with piperazine,
followed by crystallization from a ternary solvent system,
afforded the clinical candidate MK-7145, which we have
°C allowed for complete conversion of the epoxide to MK-
7
145:14 in a 4.2:1 ratio (Scheme 5). Cooling the reaction
mixture and adding water led to complete rejection of the
undesired regioisomer and allowed for isolation of MK-7145 in
7
5% yield. Recrystallization from the same solvent system
afforded the API in 92% yield and high purity with only 5 ppm
residual palladium. This sequence was ultimately run on scale
to afford >50 kg of MK-7145 and supply sufficient quantities of
active pharmaceutical ingredient to carry out all preclinical and
Phase I testing.
C
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synthesized on >50 kg scale. Future studies will describe
investigation of an alternative approach to the API to establish
a process that provides MK-7145 in high regio-, enantio-, and
diastereopurity prior to crystallization.
organic layers were washed with 10% NaCl solution (2 × 200
kg). The organic layer was filtered through Na SO (47.6 kg)
2
4
and washed with additional MTBE (20 kg). The resulting
solution was concentrated to (∼3 V) below 30 °C, and the
temperature was adjusted to 55−59 °C to afford a
homogeneous solution. n-Heptane (62.4 kg) was added
dropwise at 55−59 °C and the mixture was stirred at 55−59
EXPERIMENTAL SECTION
General. All reagents were used without further purifica-
tion. Products were authenticated against commercially
available or previously described reagents.
■
°
C for 2 h. The reaction mixture was cooled to 30−35 °C, and
3b,c
n-heptane (130.6 kg) was added dropwise over 6 h. After
stirring at 30−35 °C for an additional 1 h, the reaction mixture
was cooled to 5−10 °C and stirred for an additional 2 h. The
solids were filtered, washed with heptane (70 kg), and dried to
afford 6-bromo-3-hydroxy-2-methylbenzenemethanol (7) as a
white solid (87.06 kg, 96.2 wt %, 80.5% corrected yield).
HPLC area
percent was established on an Agilent 1100 liquid chromatog-
raphy system with a Zorbax Eclipse Plus C18 column (50 mm
×
4.60 mm, 1.8 μm) at 25 °C and flow rate of 1.5 mL/min and
λ = 210 nm. A = 0.1% phosphoric acid in HPLC water; B =
acetonitrile: gradient 90% A, 10% B to 5% A, 95% B over 5
min. wt% was calculated via sample of unknown purity
standard concentration HPLC peak area comparison against a
pure reference of known concentration.
6
-Hydroxy-7-methyl-1(3H)-isobenzofuranone (12)
[
6
1
6553−26−0]. THF (1380 kg) and compound 7 (140 kg,
45 mol, 1.0 equiv) were charged to a vessel under nitrogen at
5−25 °C and stirred 30 min until all solids dissolved.
Pd(OAc) (3 kg, 13.4 mol, 2.0 mol %), dppp (6.5 kg, 15.8 mol,
3
-Hydroxy-2-methylbenzenemethanol (6) [54874−
6−9]. THF (560 kg) and 3-hydroxy-2-methylbenzoic acid
5, 80.0 kg, 526 mol, 1 equiv) were charged into a vessel under
2
2
2
.4 mol %), and NaOAc (106 kg, 1290 mol, 2.0 equiv) were
(
subsequently charged to the same vessel. The batch was heated
nitrogen. The vessel was cooled to 10−15 °C. THF (1040 kg)
and sodium borohydride (30.1 kg, 796 mol, 1.51 equiv) were
charged to a second vessel, which was cooled to 8−10 °C. The
solution of compound 5 was added dropwise to the sodium
borohydride solution at 10−17 °C and stirred for an additional
to 128−132 °C and pressurized with carbon monoxide to
0
4
.55−0.65 MPa for 24 h. The temperature was cooled to 30−
0 °C and active carbon (14 kg) was added. The mixture was
warmed to 50−60 °C for 1.5 h. After filtration, the mixture was
concentrated to 400−500 L (3.0×) below 40 °C. Ethyl acetate
2
.0 h at 10−15 °C. Boron trifluoride diethyl etherate (129.7
(
568 kg) was added, and the mixture was concentrated to 257
kg, 914 mol, 1.74 equiv) was added to the mixture slowly over
L (3.0×) below 40 °C. Ethyl acetate (2322 kg) was added, the
temperature was adjusted to 20−30 °C and the reaction
mixture was stirred for 60 min. The organic layer was washed
with water (825 kg). The aqueous layer was then extracted
with ethyl acetate (928 kg). The combined organic layers were
washed with 7% aqueous sodium bicarbonate (403 kg) and
10% brine (840 kg). The organic layer was filtered through
8
1
h. The reaction mixture was stirred for an additional 18 h at
0−15 °C before cooling to 5−10 °C. Methanol (54.6 kg) was
then added at 5−10 °C, and the mixture stirred for 3 h at 5−10
°
C. 2% Na CO solution (1045 kg) was added slowly at 5−15
2
3
°
C to achieve pH = 7, and the mixture was stirred for an
additional 2 h at 10−20 °C. The mixture was then
concentrated under vacuum below 45 °C to 800−960 L
(
(
10.0−12.0×). The aqueous layer was extracted 3× MTBE
650 kg, 350 kg, 300 kg). The combined organic layer was
Na SO (30 kg), and the filtrate was concentrated to 400−500
2 4
L (4.0×) below 50 °C. The temperature was adjusted to 30−
35 °C, and n-heptane (678 kg) was added slowly. The reaction
mixture was cooled to 10−15 °C and stirred for 3−3.5 h. The
solids were filtered, washed with heptane (120 kg), and dried
to afford 6-hydroxy-7-methyl-1(3H)-isobenzofuranone (12) as
a white solid (85 kg, 95.5 wt %, 80.3% corrected yield).
Bromoketone 3 via Triflate 13. Dichloromethane (1298
kg) and compound 12 (85 kg, 518 mol, 1.0 equiv) were
charged to a vessel under nitrogen and stirred for 30 min at
15−25 °C. Triethylamine (84 kg, 830 mol, 1.6 equiv) was
added in one portion, and the reaction mixture was cooled to
washed with 10% brine (322 kg). The organic layer was filtered
through a pad of Na SO (16 kg) and concentrated to 300−
3
2
4
50 L (3.5−4.5×) under vacuum below 45 °C. 400 kg (4.0−
.0×) n-heptane was added and the mixture was concentrated
5
to 320−400 L (4.0−5.0×) under vacuum below 45 °C. The
vessel was cooled to 0−10 °C and stirred for 2 h. The
suspension was filtered, and the resultant cake was washed with
6
0 kg of n-heptane. 3-Hydroxy-2-methylbenzenemethanol (6)
was isolated as a white solid (65.75 kg, 99.7 LCAP, 98.5 wt %,
0.5% corrected yield).
-Bromo-3-hydroxy-2-methylbenzenemethanol (7)
9
6
3−8 °C. Tf O (162 kg, 574 mol, 1.1 equiv) was added
2
[
1255206−72−4]. To a vessel containing acetonitrile (474
dropwise while maintaining the temperature at 3−8 °C. The
mixture was stirred for an additional 20 min at 3−8 °C, and
water (380 kg) was added. The reaction mixture was warmed
to 20−30 °C and stirred for an additional 20 min. The phases
were separated, and the organic layer was washed with water
three times (456 kg, 404 kg, 454 kg). The organic layer was
filtered through Na SO (56 kg), and the solids were washed
kg) were added compound 6 (68.8 kg, 498 mol, 1.0 equiv) and
trifluoroacetic acid (439.4 kg) The vessel was cooled to −45.5
°
C under nitrogen and N-bromosuccinimide (NBS) (3 × 27.5
kg, 1 × 6.2 kg, 88.7 kg, 478 mol, 0.96 equiv) was added in 4
portions over 2 h at −45 °C. The mixture was stirred for an
additional 40 min at −43 to −30 °C. 26% NaOH solution
2
4
(
611 kg) was added to the reaction mixture via vacuum
with dichloromethane (243 kg). The combined organic liquors
were concentrated to 127−212 L (1.5−2.5×) below 40 °C,
and the KF value was measured (≤0.2%). DMF was added
(780 kg), and the solution, containing triflate 13, was
concentrated to 722−765 L (8.5−9.0×) below 40 °C.
between −5.1 and −19 °C to achieve pH 8.0. The mixture was
stirred at −10 to −20 °C for an additional 30 min, then
concentrated to 756−825 L (11−12×) below 45 °C. The
temperature was adjusted to 15−25 °C, and MTBE (330 kg)
and water (277 kg) were added to the vessel. Stirring was
continued at 15−25 °C for 30−60 min until the solids
dissolved. The phases were separated, and the aqueous layer
was extracted with MTBE (2 × 166 kg). The combined
Pd(OAc) (2.36 kg, 11 mol, 2.0 mol %) and dppp (5.05 kg,
2
12.2 mol, 2.4 mol %) were added, and the mixture was stirred
for 20 min at 20−30 °C. Triethylamine (59.8 kg, 591 mol, 1.14
equiv) and n-butyl vinyl ether (261 kg, 2610 mol, 5.0 equiv)
D
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were added to the reaction mixture, and the batch was heated
4.5×) below 40 °C. Ethyl acetate (862 kg) was added, and it
was concentrated to 340−437 L (3.5−4.5×). GC analysis
indicated assay of IPA% ≤ 10.9%. Ethyl acetate (862 kg) was
added, and the organic layer was washed with water (2 × 300
kg). The organic layer was concentrated to 340−437 L (3.5−
4.5×) under vacuum at T ≤ 42 °C, with addition of more ethyl
acetate and subsequent concentration to azeotope off water
and achieve KF = 0.2%. Ethyl acetate (715.2 kg) was added,
the mixture was warmed to 28−32 °C, and Ecosorb C-941
(6.75 kg) was added. The mixture was stirred at 28−32 °C for
35 min, followed by filtration through Celite (20 kg) at 25−30
°C and washing of the cake with ethyl acetate (110 kg). The
filtrate was concentrated to 272−340 L (2.8−3.5×) below 42
°C. The mixture was warmed to 60−70 °C until all the solids
were dissolved, and n-heptane (137 kg) was added dropwise to
the mixture at 60−70 °C until the solid was precipitated. The
mixture was cooled to 20−30 °C over 3 h, and n-heptane (634
kg) was added dropwise into the mixture over 4.3 h. The
mixture was then cooled and stirred at 0−10 °C for 90 min.
The suspension was filtered, and the cake was washed with n-
heptane (131 kg). The cake was dried at 35−40 °C under
vacuum for 18 h to give 4-methyl-5-(2R)-2-oxiranyl-1(3H)-
isobenzofuranone (4) (56.6 kg, 99.7 LCAP, 82.3% yield).
MK-7145 (1). DMAc (242 kg) was charged to a vessel
and degassed with nitrogen. Piperazine (12.43 kg, 144 mol, 1.0
equiv) and compound 4 (51.6 kg, 271 mol, 1.9 equiv) were
added to the solution under nitrogen. The mixture was heated
to 128−137 °C over 1 h under and stirred at temperature for
18 h. The reaction mixture was cooled to 50−60 °C, and water
(129 kg) was added dropwise, followed by DMAc/water (wt/
wt = 1:4, 129 kg). The mixture was cooled to 10−25 °C over 1
h and stirred for an additional 1 h. The suspension was filtered,
and the wet cake was washed with 140 kg of DMAc/water
to 80−85 °C for 3 h. The reaction mixture was cooled to 10−
1
5 °C. Ethyl acetate (912 kg) and water (460 kg) were added
to the vessel, and the temperature was cooled to 10−15 °C.
The layers were separated, and the aqueous layer was extracted
with ethyl acetate (858 kg). The combined organic layers were
washed twice with water (400 kg, 423 kg), and the organic
layer was concentrated to 127−212 L (1.5−2.5×) below 40
°
C. THF was added (936 kg), and the mixture was
concentrated to about 383−425 L (4.5−5.0×) below 40 °C
under vacuum. Water (104 kg) was added, and the mixture was
cooled to 0−5 °C. NBS (103 kg, 579 mol, 1.1 equiv) was
added in portions slowly, with the inner temperature
maintained below 15 °C during the addition and 30 min
thereafter. 48% HBr (1.0 kg) was added to adjust the pH value
to 3−4. Water (530 kg) was added slowly, and the reaction
mixture stirred at 15−20 °C for 20 min. Additional water (700
kg) was added slowly, and the mixture was cooled to 5−10 °C
for 30 min. The suspension was filtered, and the cake was
washed with cooled water (170 kg). The wet cake was
dissolved in ethyl acetate (1550 kg), and the mixture was
heated to 50−60 °C for 30 min. Active carbon (9.2 kg) was
added, and the mixture was heated to 60−70 °C for 30 min.
The suspension was filtered, and the cake was washed with
ethyl acetate (96.2 kg) through Celite (8.8 kg). The filtrate was
concentrated to 467−552 L (5.5−6.5×) below 40 °C. The
mixture was then heated to 60−70 °C to dissolve all the solids.
n-Heptane (330 kg) was added dropwise at 60−70 °C until
there was solid precipitated, and the mixture was cooled slowly
to 25−30 °C over 5 h. Additional n-heptane (706.6 kg) was
added dropwise, after which the mixture was cooled to 0−10
3
c
°C over 3 h. After stirring for an additional 2 h, the solids were
filtered and washed with n-heptane (138 kg). The cake was
dried at 20−26 °C for 12−14 h in vacuum to give active
bromoketone 3 as a white solid (98.9 kg, 98.2 wt %, 71%
yield).
(
≤
7
1:4). The wet cake was dried in an oven at 45−50 °C until KF
1.0%, which has afforded compound 1 (47.2 kg, 99.7 wt %,
4.6% yield). The API (47.2 kg) was recrystallized from DMAc
512 kg), toluene (248 kg), and water (558 kg), with heating
(
4
-Methyl-5-(2R)-2-oxiranyl-1(3H)-isobenzofuranone
at 80−110 °C, followed by cooling to room temperature to
(
(
4) [1255206−70−2]. Water (978 kg) and K HPO ·3H O
16.5 kg) were charged to a vessel and stirred until all the
2
4
2
obtain MK-7145 as an off-white solid (43.375 kg, 99.9 LCAP,
1
9
1.8% corrected yield). The H NMR spectrum was consistent
solids dissolved. H PO (2.1 kg) was added dropwise at 15−25
3
4
with the literature report.
°
C to adjust the pH to 7.0. This buffer solution (501 kg) was
transferred to a new vessel, to which was also added compound
(97 kg, 361 mol, 1.0 equiv) under nitrogen. IPA (756 kg)
3
ASSOCIATED CONTENT
sı Supporting Information
■
was then charged followed by NADP+ (3.88 kg) and Codexis
KRED-MIF-20 (3.88 kg), and the mixture was stirred for 1 h at
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00314.
1
5−25 °C until all the solids were dissolved. The remaining
buffer solution was transferred to the vessel, and the mixture
was warmed to 28−33 °C and stirred for 6 h. The batch was
cooled to 22 ± 2 °C. and 36.3% aqueous K CO solution (162
kg) was added dropwise at 20−25 °C over 3 h, followed by
stirring for an additional 3 h. Na SO (50 kg) was charged in
Full characterization of specified impurities is provided,
1
along with MK-7145 HPLC and H NMR spectral data
2
3
(PDF)
2
4
portions, the mixture was stirred for 30 min and then cooled to
AUTHOR INFORMATION
0
−10 °C. H PO (31.7 kg) was added to the vessel, and the
■
3
4
pH was measured as 7.33 after 30 min. Ethyl acetate (893 kg)
Corresponding Author
was added, and the reaction mixture stirred for 30 min at 20−
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
3
0 °C. The aqueous layer was removed. Ethyl acetate (1213
kg) was added to the emulsification layer in the original vessel.
The reaction mixture was stirred for 40 min at 20−30 °C, and
the aqueous layer was removed. The emulsification layers were
combined, filtered, and centrifuged, and the aqueous layer was
separated. 17% aqueous Na SO solution (340 kg, 180 kg) was
Authors
Qinghao Chen − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United States;
orcid.org/0000-0001-5735-4019
2
4
added twice into the organic layer, stirred, and separated. The
resultant organic layer was concentrated to 340−437 L (3.5−
E
https://dx.doi.org/10.1021/acs.oprd.0c00314
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
Nelo Rivera − Process Research & Development, MRL, Merck
(5) Use of acetic acid instead of trifluoroacetic led to increased
formation of regioisomer 8 (17%) and dibromide 9 (11%).
&
Co., Inc., Rahway, New Jersey 07065, United States;
(6) For more information on CuCN cyanation reactions, see: Ellis,
orcid.org/0000-0001-7491-0662
G. P.; Romney-Alexander, T. M. Cyanation of aromatic halides. Chem.
Jongrock Kong − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United States
Ian K. Mangion − Process Research & Development, MRL,
Merck & Co., Inc., Rahway, New Jersey 07065, United States
Lushi Tan − Process Research & Development, MRL, Merck &
Co., Inc., Rahway, New Jersey 07065, United States
Rev. 1987, 87, 779−794.
(7) For a review on palladium-catalyzed carbonylation reactions, see:
Barnard, C. F. J. Palladium-Catalyzed Carbonylation − A Reaction
Comes of Age. Organometallics 2008, 27, 5402−5422.
(8) A small screen of bidentate phosphine ligands (dppp, dppe, dppf,
dtbpf), solvents, and bases was conducted to arrive at these
Fred J. Fleitz − Process Research & Development, MRL, Merck
conditions.
&
Co., Inc., Rahway, New Jersey 07065, United States
(9) Heck coupling between ethylene glycol vinyl ether and
bromoarenes has been shown to afford products with the desired
regioselectivity. Unfortunately, this synthetic approach failed to
provide direct entry into the necessary substrate. (a) Hyder, Z.;
Ruan, J.; Xiao, J. Hydrogen-Bond-Directed Catalysis: Faster,
Regioselective and Cleaner Heck Arylation of Electron-Rich Olefins
in Alcohols. Chem. - Eur. J. 2008, 14, 5555−5566. (b) Arvela, R. K.;
Pasquini, S.; Larhed, M. Highly Regioselective Internal Heck
Arylation of Hydroxyalkyl Vinyl Ethers by Aryl Halides in Water. J.
Org. Chem. 2007, 72, 6390−6396. (c) Chung, C. K.; Cleator, E.;
Dumas, A. M.; Hicks, J. D.; Humphrey, G. R.; Maligres, P. E.; Nolting,
A. F.; Rivera, N.; Ruck, R. T.; Shevlin, M. A Synthesis of a Spirocyclic
Macrocyclic Protease Inhibitor for the Treatment of Hepatitis C. Org.
Lett. 2016, 18, 1394−1397.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00314
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Thanks to Zhiguo (Jake) Song (Merck), Yang Cao (Merck),
and WuXi STA for help with impurity characterization.
ABBREVIATIONS
■
(10) (a) Cabri, W.; Candiani, I.; Bedeschi, A. Ligand-Controlled α-
Regioselectivity in Palladium-Catalyzed Arylation of Butyl Vinyl
Ether. J. Org. Chem. 1990, 55, 3654−3655. (b) Cabri, W.; Candiani,
I.; Bedeschi, A.; Penco, S. α-Regioselectivity in Palladium-Catalyzed
Arylation of Acyclic Enol Ethers. J. Org. Chem. 1992, 57, 1481−1486.
ROMK renal outer medullary potassium channel; hERG
human Ether-a-
̀
go-go-Related Gene; SAR structure activity
relationship; NBS N-bromosuccinimide; TFA trifluoroacetic
acid; CuCN copper(I) cyanide; dppp diphenylphosphinopro-
pane; KRED ketoreductase; DMAc N,N-dimethylacetamide;
API active pharmaceutical ingredient; ppm parts per million;
LCAP liquid chromatography area percent
(
c) Cabri, W.; Candiani, I.; Bedeschi, A. Palladium-Catalyzed
Arylation of Unsymmetrical Olefins Bidentate Phosphine Ligand
Controlled Regioselectivity. J. Org. Chem. 1992, 57, 3558−3563.
(11) Huisman, G. W.; Liang, J.; Krebber, A. Practical chiral alcohol
manufacture using ketoreductases. Curr. Opin. Chem. Biol. 2010, 14,
22−129.
12) For representative references on amine openings of epoxides,
see: (a) Alikhani, V.; Beer, D.; Bentley, D.; Bruce, I.; Cuenoud, B. M.;
Fairhurst, R. A.; Gedeck, P.; Haberthuer, S.; Hayden, C.; Janus, D.;
Jordan, L.; Lewis, C.; Smithies, K.; Wissler, E. Long-chain formoterol
analogues: an investigation into the effect of increasing amino-
1
(
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX