Development of a green and sustainable manufacturing process for gefapixant citrate (MK-7264) Part 2: Development of a robust process for phenol synthesis

Article abstract of DOI:10.1021/acs.oprd.0c00241

Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.

Full text of DOI:10.1021/acs.oprd.0c00241

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Article
Development of a Green and Sustainable Manufacturing Process for
Gefapixant Citrate (MK-7264) Part 2: Development of a Robust
Process for Phenol Synthesis
́
Feng Peng,* Guy R. Humphrey, Kevin M. Maloney, Dan Lehnherr, Mark Weisel, Francois Levesque,
John R. Naber, Andrew P. J. Brunskill, Patrick Larpent, Si-Wei Zhang, Alfred Y. Lee, Rebecca A. Arvary,
Claire H. Lee, Daniel Bishara, Karthik Narsimhan, Eric Sirota, and Michael Whittington
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ABSTRACT: Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are
described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation
approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After
exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-
isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol
DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant
scale with low process mass intensity and cost.
KEYWORDS: alkylation, methoxylation, phenol derivatization, copper catalysis, Gefapixant
methoxyacetophenone 2 is not a commodity chemical, and it
requires two additional steps from commodity mequinol 1 using
a Fries rearrangement (Scheme 1). Overall, this process delivers
phenol 3 with a process mass intensity (PMI)4 of more than 120.
In addition to this, the handling of TfOH at high temperatures
for the Fries rearrangement adds a significant safety concern to
this approach. Herein, we described a newly developed low-cost,
concise, and safe process of synthesizing phenol 3 from
commodity chemicals.
1. INTRODUCTION
A popular literature method of synthesizing 2-isopropyl-4-
methoxy phenol 3,1 a key building block in Gefapixant citrate
(MK-7264), is to perform a methyl Grignard addition to 2′-
hydroxy-5′-methoxyacetophenone 2 and a subsequent hydro-
genation on the resulting tertiary alcohol (Scheme 1).2 This
approach represents a common strategy to install an isopropyl
group on electron-rich aromatic rings via hydrogenation of an
aryl dimethyl tertiary alcohol.3 However, 2′-hydroxy-5′-
2. RESULTS AND DISCUSSION
Scheme 1. Synthesis of 2-Isopropyl-4-methoxyphenol and
Structure of Gefapixant Citrate (MK-7264)
2.1. Route Scouting. Although the criteria for a commercial
route vary from one company to another, there are several
common principles such as low cost, ease of operation, safety,
ease of supply, robustness, and sustainability that are typically
considered important.5 Guided by these principles, we sought to
define a concise, protecting-group-free, and precious-metal-free
route to achieve a cost-effective and environmentally benign
process to synthesize phenol 3 from commodity chemicals.
Herein, we describe our route scouting efforts to phenol 3 with
three different approaches.
The first approach (Scheme 2A) uses 6-methoxy-4-methyl-
coumarin 4 as the starting material, which provides 2-isopropyl-
4-methoxyphenol 3 in a single step with good yield under high-
Received: May 22, 2020
https://dx.doi.org/10.1021/acs.oprd.0c00241
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© XXXX American Chemical Society
A

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Article
Scheme 2. Coumarin Fragmentation Reaction to Provide Phenol 3
temperature flow conditions.6 6-Methoxy-4-methylcoumarin 4
is not a commodity and cost-effective building block, and
Pechmann condensation7 using 1 and 2 provided a low yield of 3
in batch conditions in hand. In order to further improve process
efficiency, we also investigated the possibility to synthesize 4 in
flow and telescope the formation of coumarin 4 with the phenol
synthesis (Scheme 2B). This approach was complicated by the
low yield in the coumarin formation step, which provides a low
conversion reaction in flow.
Previously, Takai and co-workers reported Re2(CO)10 as an
effective catalyst for the ortho-monoalkylation of phenols using
terminal alkenes such as 1-octene to afford the branched
hydroarylation product 4 (Scheme 4A).12 Intrigued by Takai’s
Scheme 4. Recatalyzed Isopropylation of Mequinol
Our second approach uses mequinol 1 as the starting material.
Retrosynthetically, a Friedel−Crafts reaction between mequinol
and an isopropyl cation would provide 2-isopropyl-4-methox-
yphenol (Scheme 3). Not surprisingly, this reaction was
Scheme 3. Synthesis of 3 via Friedel−Crafts Isopropylation of
Mequinol 1
report with high-boiling alkenes (e.g., bp of 1-octene = 122 °C),
we explored isopropylation using low-boiling alkenes, in
particular using propene (bp, −48 °C). Indeed, this approach
proved successful in affording 3 directly from mequinol and
propene and provided a very clean reaction profile. Upon further
optimization of the reaction temperature and pressure, guided
by our recent study of the reaction mechanism,13 we
demonstrated a 100 g isopropylation of mequinol with 91%
yield and 0.5 mol % catalyst loading (Scheme 4B).
The synthesis of 3 as described in Scheme 4B is a synthetically
attractive route since it utilizes commodity feedstock materials
and provides the desired phenol in one step; however, the use of
expensive Re2(CO)10 significantly increased the cost of this
route.14 In addition, this route requires high temperature and
high pressure, which limits its execution to manufacturing sites
with specialized equipment to handle these conditions. In view
of these limitations, we sought a new approach for the synthesis
of phenol 3.
reported to afford a complex reaction profile and low yield
due to an overalkylation side reaction of 3.8 However, we were
inspired by the simplicity of this proposal and quickly leveraged
high-throughput experimentation (HTE) to evaluate this
approach.9
Our initial screening of Lewis acids, isopropyl cation
precursors, solvents, and different reaction temperatures did
not provide a clean reaction profile for isopropylation of
mequinol.10 In most cases, overalkylation products dominated
the product mixture. This observation is consistent with
literature reports since phenol 3 is more electronically rich
than mequinol, and product 3 would also react with the
isopropyl cation to provide overalkylation products.8 In order to
achieve a clean isopropylation of mequinol, it was thought that
conditions not involving a classic isopropyl cation mechanism
could provide better results. We therefore tested transition-
metal catalysts, hoping that a C−H activation and hydro-
arylation would provide the desired phenol product.11 Despite
broad screening of transition-metal catalysts, rhenium-based
catalysts, specifically Re2(CO)10, proved uniquely effective.
While the first two approaches described above prepare
phenol 3 through installation of the isopropyl group on a fully
functionalized aromatic ring, the third approach that we
considered features methoxylation of isopropylphenol 5, a
B
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commodity chemical (Scheme 5). As such, a regioselective
bromination of phenol 5 provides para-bromoisopropylphenol
Scheme 6. Rational for Regioselective Outcome Dependent
on Solvent
Scheme 5. Bromination and Methoxylation of 2-
Isopropylphenol 5
6 in high yield. Cu-catalyzed methoxylation (formally an
Ullmann methyl aryl ether synthesis) provides our desired
phenol in about 75% yield.15 In addition, these two steps could
be telescoped in a one-pot process.16 Since this approach
appears to meet several criteria for a manufacturing route, such
as cheap commodity starting materials, inexpensive reagents,
and promising levels of efficiency, we decided to investigate it in
greater detail.
2.2. Process Optimization. Our first objective was to
identify the best conditions for preparing para-bromophenol 6.
A quick survey of popular bromination conditions in different
solvents revealed that several brominating reagents provide
para-bromophenol 6 with excellent yields (Table 1).17 For
hydroxyl, thus preventing the phenol−NBS interaction shown in
Scheme 6 that leads to ortho-bromination. With these optimized
conditions in hand, the bromination reaction robustly provides
desired bromophenol 6 in 95% assay yield (AY), along with 1−
2% dibromophenol 8 and 1% ortho-bromophenol 7.
Table 1. Summary of Bromination Outcomes Using Phenol 5
Our next objective was to develop a robust Cu-catalyzed
methoxylation process to provide highly pure 2-isopropyl-4-
methoxyphenol 3. Our initial conditions (Scheme 5) provided
2-isopropyl-4-methoxyphenol in about 75% yield in which
dimer 9 and isopropylphenol 5 were generated in high levels, up
to 20% total. Oxidative dimer 9 is probably formed via a Cu-
catalyzed phenol oxidative coupling of the electron-rich phenol
by trace oxygen.20 We wondered if these side reactions could be
suppressed by tuning the reaction conditions. To test this
hypothesis, we screened a range of different solvents, copper
precatalysts, additives, and ligands.21 Several conditions were
identified as leads due to their favorable product distribution
observed at a screening scale (20 μmol). For example,
additivessuch as methyl formate, ethyl acetate, and DMF
(entries 1−5)were found to suppress isopropylphenol 5 from
22% down to 4% (entry 5). CuBr performed better than CuCl
and CuI under the same conditions (entry 1 vs entry2, entry 3 vs
entry 4, entry 8 vs entry 13 vs entry 14). Ligands,22 particularly
dicarbonyl compound L2 (entry 8), were discovered to decrease
the formation of oxidative dimer 9 from 18% down to 4%
(entries 6−13) and NaOMe was demonstrated as the best base
(entries 15−20). Combining these findings, the methoxylation
reaction provided greater than 90% yield of 3 when the reaction
was run inside a N2-filled glovebox (entry 16).
2.3. First Generation of Cu-Methoxylation Process.
With the lead conditions in hand (Table 2, entry 16), we scaled
up the Cu-catalyzed methoxylation reaction to a 50 g scale inside
a fume hood (i.e., outside of a glovebox). To our surprise, the
dimer impurity increased significantly, even when taking
extreme precautions to degas the reaction mixture by sparging
(30 min of heavy sparging with N2 per 20 mL of reaction
mixture) prior to addition of the NaOMe. Additionally, the end
of the reaction stream was discovered to be unstable as the level
of the oxidative dimer 9 continued to increase during storage.
Since the formation of oxidative dimer 9 likely involves
entry
reagent
Br2
NBS
solvent
6 (LCAP) 7 (LCAP) 8 (LCAP)
1
2
3
4
5
6
CH2Cl2
MeCN
toluene
MeCN
toluene
MeCN
85
96
25
93
94
88
7
1.8
73
1
4
1.5
8
2.2
2
6
2
NBS
HBr + H2O2
PyHBr3
PyHBr3
10.5
example, HBr in DMSO, Br2, NBS, and PyH-Br3 all provide
desired bromophenol 6 with good yields. Considering the cost
and ease of reagent handling, we chose NBS as the bromination
reagent. During this investigation, it was also found that solvent
plays a critical role in the regioselectivity of bromination. For
example, with NBS in MeCN, the desired para-bromophenol 6
was obtained in 96% yield. On the other hand, when performing
the reaction in toluene, the undesired ortho-bromophenol 7 was
the major product. This interesting observation could be
explained by hydrogen bonding between phenol and NBS in
nonpolar solvents (such as toluene), which facilitates a closed
transition state to brominate ortho to the hydroxy group
(Scheme 6). On the other hand, when MeCN is used, a
hydrogen bonding interaction between the phenol and MeCN
causes the bromination to occur at the less-hindered para-
position as sterics become the dominant factor.18 The quality of
NBS also played a critical role as some new batches of NBS
provided significant dibrominated side product 8. This side
reaction was suppressed by the addition of 1 mol %
methanesulfonic acid (MSA) in the reaction medium.19 We
hypothesize that MSA disables the path to ortho-bromination
due to it being a better hydrogen bond donor than the phenol
C
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Table 2. Summary of Cu-Catalyzed Methoxylation of 2-Isopropyl-4-bromophenol Screens
entry
Cu source
ligand
additive
base
3 (LCAP)
5 (LCAP)
9 (LCAP)
10 (LCAP)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
CuCl
CuBr
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Cul
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
N/A
N/A
N/A
N/A
L1
L1
L2
L3
L4
L5
L6
L2
L2
L2
L2
L2
L2
none
none
HCO2Me
HCO2Me
DMF
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
K3PO4
42
57
69
74
80
42
84
91
80
75
79
82
87
85
51
94
56
62
75
93
26
22
7
5
4
27
4
4
6
9
7
8
5
6
22
3
18
15
19
4
28
18
22
18
14
28
11
4
12
13
12
8
2
3
2
3
2
3
1
1
2
3
2
2
2
3
3
1
3
3
1
1
none
HCO2Me
HCO2Me
HCO2Me
HCO2Me
HCO2Me
HCO2Me
HCO2Me
HCO2Me
HCO2Me
HCO2Me
DMF
8
8
24
2
23
20
5
NaOMe
K3PO4
Cs2CO3
LiOMe
KOMe
L2
L2
L2
DMF
DMF
DMF
2
coordination between Cu and the para-methoxyphenoxide
anion, we postulated that a protecting group on the phenol may
prevent this coordination, which would suppress the formation
of dimer 9. Indeed, the use of an in situ protection with a THP
group enabled a ligand-free Cu-catalyzed methoxylation of
bromophenol 6 in high yield with the formation of the dimer
being suppressed to less than 0.1%23 and the THP can be
deprotected during an aqueous HCl workup, without the need
for an additional step (Scheme 7). This three-step trans-
To our disappointment, this investigation indicated that several
impurities that were present in small amounts in 3 could not be
rejected well in the downstream steps (e.g., ortho-bromophenol
7, dibromophenol 8, and 2-isopropylphenol 5), which suggests
that these impurities need to be controlled to lower levels as part
of the phenol synthesis. In view of the need for higher purity
materials, a robust crystallization of 2-isopropyl-4-methoxyl-
phenol 3, or one of its derivatives, would be an ideal solution to
this challenge. However, although it was soon found that phenol
3 itself is a crystalline solid with an m.p. of 35 °C, unfortunately,
attempts to recrystallize this material directly suffered from high
mother liquor losses under all isolation conditions examined
(e.g., heptane/toluene, hexane/toluene, and MeOH/water). In
addition, the low melting point of 3 also frequently caused
oiling-out of the product on the filter during isolation. Thus, to
achieve this objective, we sought to identify a more suitable
crystalline solid form of phenol 3. A crystalline potassium salt
was discovered; however, this type of phenol derivative was
found to be unstable in the presence of oxygen. In addition,
several oxidative impurities were identified upon stress studies of
these crystallization conditions. This highlights that a robust
crystallization process is challenging to achieve with electron-
rich 2-isopropyl-4-methoxyphenol. To our delight, we even-
tually discovered that crystallization of phenol with DABCO,
corresponding to a bromophenol-DABCO cocrystal 12 (mp =
95−97 °C),24 provided a robust isolation point and stable,
Scheme 7. First Generation Approach to Phenol 3 Enabled by
a THP Protecting Group
formation was telescoped in a one-pot process, providing the
desired phenol in 96% yield at the 50 g scale with less than 0.1%
of the phenol oxidative dimer byproduct being formed.
2.4. Impurity Control and Second Generation Cu-
Catalyzed Methoxylation Process. With the optimized
process shown in Scheme 7, we then evaluated if phenol 3 from
this new process could be used to produce API in good quality.
D
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highly crystalline intermediate.25 This process upgrades the
purity of bromophenol to 99.8 LCAP, which reproducibly
controls the problematic impurities to low levels. As a result,
phenol 3 from the new process can be used to produce API with
good quality. This bromophenol-DABCO cocrystal tends to
have a large particle size (D50 = 370 μm) and is observed to have
dense packing (d = 0.9 g/mL). These properties provide heavy
solid particles, which raised the risk of difficulty dispersing
suspensions that could cause plugging concerns at the plant scale
when piping the slurry. To mitigate this risk, we found that by
lowering the crystallization temperature from 60 to 30 °C,
smaller particle size crystals (D50 = 180 μm) can be obtained as a
result of reducing growth rate kinetics while maintaining a high
supersaturation (Figure 1).26
conditions or the use of a glovebox. This new process was
ultimately demonstrated successfully at the plant scale with the
same yield and profile as the lab scale (Scheme 8). Overall, the
new process delivered phenol 3 with a PMI of 23, which
significantly reduces waste generation compared with the initial
four-step process (PMI = 127) and provides a shorter, simpler
process. To date, 3 tons of phenol 3 has been prepared through
this new process.
To understand the role of DABCO and DMF in this process,
we studied the control reactions in toluene without DABCO and
DMF. The kinetic data indicates that both DMF and DABCO
accelerate the C−O coupling compared to the reaction without
these additives (Figure 2). Interestingly, the data also suggests
Figure 1. Controlling bromophenol-DABCO crystal particle size
through temperature.
Figure 2. Impact of DABCO on reaction conversion.
With a robust process for isolating the bromophenol-DABCO
salt 12, we sought to convert this species to the THP-protected
bromophenol 11 to bridge with the previous phenol process
(Scheme 7). We initially subjected the bromophenol-DABCO
cocrystal intermediate to the standard protection conditions of 1
equiv DHP and a catalytic amount of camphorsulfonic acid
(CSA, 5 mol %). Not surprisingly, this transformation provided
poor conversion since CSA is neutralized by DABCO. In
contrast, when the bromphenol-DABCO complex was first
subjected to an acidic workup (using aq HCl) to provide free
bromophenol 6 in toluene, the DHP protection step proceeded
as expected to cleanly deliver THP-protected bromophenol 11.
However, this approach adds one more operation to the process.
For the sake of simplicity and cost, it was deemed optimal that
the bromophenol-DABCO cocrystal undergoes methoxylation
directly without the use of THP protection. While this was a very
attractive proposal, we realized that generation of a free
phenoxide anion27 under NaOMe conditions could potentially
provide oxidative dimer 9 via coordination with a high valent
copper catalyst. Nevertheless, to our delight, the methoxylation
reaction of the bromophenol-DABCO cocrystal 12 provides 3
with a clean reaction profile, in up to 98.8 LCAP. Using 12 as the
starting material led to formation of less than 0.1 LCAP of the
oxidative dimer without the need for rigorously air-free
that DABCO suppresses dimer formation, regardless of whether
running the reaction in a glovebox or in a fume hood. Without
DABCO, reactions tend to provide high levels of dimer 9,
namely, 6 and 18 LCAP for reactions carried out in the glovebox
and fume hood, respectively. Based on these observations, we
propose that DABCO serves as a unique ligand for Cu.28 Upon
coordination with Cu, DABCO not only facilitates the C−O
bond formation reaction but also suppresses coordination of the
phenoxide to Cu due to the steric hindrance between DABCO
and the isopropyl group. As such, the resulting C−O formation
reaction provides low levels of dimer 9.
3. CONCLUSIONS
In summary, we utilized a blend of rational design and HTE to
develop a green and robust two-step process for synthesizing
phenol 3 from commodity chemicals. The key discovery was
bromophenol-DABCO cocrystal 12, which not only provided an
efficient impurity control point but also enabled a robust Cu-
catalyzed methoxylation reaction by suppressing the formation
of the phenol dimer. The new process was demonstrated
successfully at several different sites on the plant scale with
almost 2 times improvement in yield and an 80% reduction in
PMI compared with the initial four-step process.29
Scheme 8. Plant Demonstration of a New 2-Isopropyl-4-methoxylphenol Process
E
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3.1. Experimental Section. Unless otherwise noted, all
reactions were performed under a nitrogen atmosphere. All
reagents and solvents were commercially available and used
without further purification unless indicated otherwise. Yields
reported are for isolated, spectroscopically pure compounds.
NMR spectra were recorded on Bruker 400 or 500 MHz
instruments. The residual solvent protons (1H) or the solvent
carbons (13C) were used as internal standards. 1H NMR data are
presented as follows: chemical shift in ppm downfield from
tetramethylsilane (multiplicity, coupling constant, integration).
The following abbreviations are used in reporting NMR data: s,
singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; qt,
quartet of triplets; dd, doublet of doublets; dt, doublet of triplets;
AB, AB quartet; and m, multiplet. High-resolution mass spectra
were recorded by the on a Waters Xevo G2 Qtof spectrometer.
Assay yield was measured via the external pure standard.
3.1.1. Preparation of Phenol 3 Using Rhenium Catalyst. To
a high-pressure vessel were charged 400 mL of anhydrous
toluene, Re2(CO)10 (3.16 g, 4.84 mmol), and mequinol 1 (100
g, 806 mmol) at RT. The vessel was then degassed with
propylene and charged with propylene (85.0 g, 2.02 mol). The
vessel was sealed and heated to 170 °C. Internal pressure was
measured near 250 psi. The reaction was stirred under these
conditions for 72 h. The vessel was then allowed to cool down to
23 °C. The internal pressure was carefully released to 1
atmosphere pressure, and the toluene solution was assayed as 91
wt % of phenol 3.
mol). The reaction mixture was then degassed with N2 at RT. To
the reactor was charged CuBr (3.2 kg, 22 mol) and the reaction
was agitated at 88 °C overnight. The batch was cooled to 5 °C
and 220 L of HCl (6 N in water) was charged over 25 min under
N2. The product was extracted with 480 L of toluene (4 V) at
room temperature. This stream was directly used in the next
step. For characterization, the organic layer was concentrated
and the product was isolated as a yellowish oil (71 kg, 98.2 NMR
wt %, 95% yield). This oil was further purified via column
chromatography. Pure product is a crystalline solid (m.p. = 34−
35 °C). 1H NMR (500 MHz, CDCl3): δ 6.82 (dt, J = 3.2, 1.5 Hz,
1H), 6.71 (d, J = 8.6 Hz, 1H), 6.64 (dd, J = 8.6, 3.0 Hz, 1H), 4.50
(s, 1H), 3.80 (t, J = 1.2 Hz, 3H), 3.23 (heptet, J = 10.4, 9.2, 5.2,
1.7 Hz, 1H), 1.28 (s, 3H), 1.27 (s, 3H); 13C NMR (126 MHz,
CDCl3): δ 153.9, 146.8, 135.9, 115.8, 112.8, 110.9, 55.8, 27.3,
22.6; HR-MS: [M + H]+ calcd for C10H15O2 , 167.1054; found,
+
167.1027.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00241.
■
sı
Additional experimental details, NMR spectra, mass
spectrometry data, and HPLC traces (PDF)
Crystallographic data of 4-bromo-2-isopropylphenol-
DABCO cocrystal (CIF)
3.1.2. Preparation of Bromophenol-DABCO 12. 2-Isopro-
pylphenol (90 kg, 661 mol) and acetonitrile (270 L) were
charged to a 1500 L vessel with jacket, mechanical stirrer,
temperature probe, and N2 inlet at RT. To this mixture was
charged methanesulfonic acid (429 mL, 6.6 mol). The reaction
mixture was cooled to −10 °C, and then NBS (118 kg, 661 mol)
was charged as a solid in four portions (each 29.5 kg). The
reaction temperature was maintained below −5 °C while
charging NBS. The reaction was aged for 1 h and allowed to
warm to 0 °C. It was then quenched with 0.5 wt % NaHSO3 in
water (540 L) at −5 °C and the product was extracted with
toluene (270 L) at 45 °C. The toluene layer was sequentially
washed with 5% v/v aq H3PO4 (180 L) and 5% brine (180 L).
The toluene solution was concentrated to remove water and
acetonitrile (spec. for water = 5000 ppm; spec. for MeCN = 2%,
pure bromophenol m.p. = 43−44 °C). The residual stream was
heated to 50 °C and DABCO (36.7 kg, 330 mol) was charged,
which provided a homogeneous solution. To this solution were
charged heptane (225 L), lecithin (90 g),30 and seed of product
12 (90 g). This mixture was agitated for additional 1 h at same
temperature, and then heptane (225 L) was charged over 1 h.
The resulting slurry was allowed to cool to 20 °C over 2 h and
the product was isolated by filtration. The cake was washed with
heptane (90 L) and dried under vacuum with N2 sweep (165 kg,
92% yield, m.p. = 95−97 °C).1H NMR (500 MHz, CDCl3): δ
8.75 (s, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.4, 2.5 Hz,
1H), 6.51 (dd, J = 8.5, 0.8 Hz, 1H), 3.32−3.21 (m, 1H), 2.91 (s,
6H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (126 MHz, CDCl3):
δ 153.5, 138.1, 129.4, 129.0, 117.1, 111.8, 46.2, 27.1, 22.5; HR-
AUTHOR INFORMATION
Corresponding Author
■
Feng Peng − Small Molecule Process Research and Development,
Merck & Co., Inc., Rahway, New Jersey 07065, United States;
orcid.org/0000-0002-2382-2862; Email: feng.peng@
merck.com
Authors
Guy R. Humphrey − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0001-8634-1567
Kevin M. Maloney − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0003-1422-5422
Dan Lehnherr − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0001-8392-1208
Mark Weisel − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
́
Francois Levesque − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0001-9529-4993
John R. Naber − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0002-4390-3467
Andrew P. J. Brunskill − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
MS: [M + H]+ calcd for C24H35Br2N2O2 , 543.1024; found,
+
543.1037.
Patrick Larpent − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Si-Wei Zhang − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0001-8677-3722
3.1.3. Preparation of Phenol 3 Using Cu Catalyst. At room
temperature, a jacketed reactor equipped with an overhead
stirrer and N2 inlet was charged with sodium methoxide solution
in methanol (25 wt %, 304 L, 1328 mol), DMF (60 L), and 4-
bromo-2-isopropylphenol-DABCO cocrystal 12 (120 kg, 442
F
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Yardstick. Org. Process Res. Dev. 2011, 15, 912−917. (c) Li, J.; Albrecht,
J.; Borovika, A.; Eastgate, M. D. Evolving Green Chemistry Metrics into
Predictive Tools for Decision Making and Benchmarking Analytics.
ACS Sustainable Chem. Eng. 2018, 6, 1121−1132.
(5) (a) Leng, R. B.; Emonds, M. V. M.; Hamilton, C. T.; Ringer, J. W.
Holistic Route Selection. Org. Process Res. Dev. 2012, 16, 415−424.
(b) Dach, R.; Song, J.-J.; Roschangar, F.; Samstag, W.; Senanayake, C.
H. The Eight Criteria Defining a Good Chemical Manufacturing
Process. Org. Process Res. Dev. 2012, 16, 1697−1706.
Alfred Y. Lee − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0003-3684-4101
Rebecca A. Arvary − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Claire H. Lee − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Daniel Bishara − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Karthik Narsimhan − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
(6) Phenol 3 was only observed as minor product (5% yield) when the
reaction was reported in batch mode: (a) Chang, J.; Wang, S.; Shen, Z.;
Huang, G.; Zhang, Y.; Zhao, J.; Li, C.; Fan, F.; Song, C. Ethylene glycol
as hydrogen donor for the syntheses of thymol analogues via hydrolysis
of 4-methylcoumarins. Tetrahedron Lett. 2012, 53, 6755−6757. For
̈
Mechanism: (b) Fries, K.; Fickewirth, G. Uber o-Vinyl-phenole. Chem.
Ber. 1908, 41, 367.
(7) Daru, J.; Stirling, A. Mechanism of the Pechmann Reaction: A
Theoretical Study. J. Org. Chem. 2011, 76, 8749−8755.
(8) Zenker, N.; Jorgensen, E. Synthesis of 2-Isopropyl-4-methox-
yphenol. J. Org. Chem. 1959, 24, 1351−1353.
Eric Sirota − Small Molecule Process Research and Development,
Merck & Co., Inc., Rahway, New Jersey 07065, United States
Michael Whittington − Small Molecule Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
(9) (a) Majetich, G.; Zhang, Y. Concise Synthesis of ( )-Perovskone.
J. Am. Chem. Soc. 1994, 116, 4979−4980. (b) Klemm, L. H.; Taylor, D.
R. Alumina-catalyzed reactions of hydroxyarenes and hydroaromatic
ketones. 9. Reaction of phenol with 1-propanol. J. Org. Chem. 1980, 45,
4320−4326. (c) Olah, G. A.; Kaspi, J.; Bukala, J. Heterogeneous
catalysis by solid superacids. 3. Alkylation of benzene and trans-
alkylation of alkylbenzenes over graphite-intercalated Lewis acid halide
and perfluorinated resin sulfonic acid (Nafion-H) catalysts. J. Org.
Chem. 1977, 42, 4187−4191. (d) Tateiwa, J.-i.; Nishimura, T.;
Horiuchi, H.; Uemura, S. Rearrangement of alkyl phenyl ethers to
alkylphenols in the presence of cation-exchanged montmorillonite
(Mn+−mont). J. Chem. Soc., Perkin Trans. 1 1994, 3367−3372.
(e) Sartori, G.; Bigi, F.; Maggi, R.; Arienti, A. Acidity effect in the
regiochemical control of the alkylation of phenol with alkenes. J. Chem.
Soc., Perkin Trans. 1 1997, 257−260. (f) Niggemann, M.; Bisek, N.
Calcium-Catalyzed Hydroarylation of Alkenes at Room Temperature.
Chem. − Eur. J. 2010, 16, 11246−11249.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00241
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Aldo Rancier and Wilfredo Pinto for analytical
support. We thank Ben Sherry, Matt Winston, Jenny Obligacion,
Zhijian Liu, Christopher Nawrat, Becky Ruck, and LC Campeau
for proofreading suggestions.
(10) See Supporting Information for details.
(11) (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Catalytic Functionalization
of Arenes and Alkanes via C−H Bond Activation. Acc. Chem. Res. 2001,
34, 633−639. (b) Dorta, R.; Togni, A. Addition of the ortho-C−H
bonds of phenol across an olefin catalysed by a chiral iridium(I)
diphosphine complex. Chem. Commun. 2003, 760−761.
ABBREVIATIONS
■
TLC = thin layer chromatography; NBS = N-bromosuccini-
mide; PMI = process mass intensity; V = volume; LCAP =
HPLC/UPLC area percentage; IY = isolated yield; AY = assay
yield; CSA = camphorsulfonic acid; DABCO = 1,4-diazabicyclo-
[2.2. 2]octane; DHP = 3,4-dihydropyran
(12) (a) Kuninobu, Y.; Matsuki, T.; Takai, K. Rhenium-Catalyzed
Regioselective Alkylation of Phenols. J. Am. Chem. Soc. 2009, 131,
9914−9915. (b) Kuninobu, Y.; Yamamoto, M.; Nishi, M.; Yamamoto,
T.; Matsuki, T.; Murai, M.; Takai, K. Rhenium-Catalyzed ortho-
Alkylation of Phenols. Org. Synth. 2017, 94, 280−291.
REFERENCES
(13) Lehnherr, D.; Wang, X.; Peng, F.; Reibarkh, M.; Weisel, M.;
Maloney, K. M. Mechanistic Study of a Re-Catalyzed Monoalkylation
of Phenols. Organometallics 2019, 38, 103−118.
■
(1) ((a)) Broka, C. A.; Carter, D. S.; Dillon, M. P.; Hawley, R. C.;
Jahangir, A.; Lin, C. J. J.; Parish, D. W. U.S. Patent US 2005/0209260
A1, September 22, 2005. (b) Jahangir, A.; Alam, M.; Carter, D. S.;
Dillon, M. P.; Du Bois, D. J.; Ford, A. P. D. W.; Gever, J. R.; Lin, C.;
Wagner, P. J.; Zhai, Y.; Zira, J. Identification and SAR of novel
diaminopyrimidines. Part 2: The discovery of RO-51, a potent and
selective, dual P2X3/P2X2/3 antagonist for the treatment of pain.
Bioorg. Med. Chem. Lett. 2009, 19, 1632−1635.
(14) The price of Re2(CO)10 in 2017 was 36,000 $/kg.
(15) For an alternative approach to install a para-methoxyl group on a
phenol, see: (a) Amant, A. H. S.; Frazier, C. P.; Newmeyer, B.;
Fruehauf, K. R.; de Alaniz, J. R. Direct synthesis of anilines and
nitrosobenzenes from phenols. Org. Biomol. Chem. 2016, 14, 5520−
5524. For a review on Ullmann ether synthesis, see: (b) Lindley, J.
Tetrahedron report number 163 : Copper assisted nucleophilic
substitution of aryl halogen. Tetrahedron 1984, 40, 1433−1456.
(c) Peng, F.; McLaughlin, M.; Liu, Y.; Mangion, I.; Tschaen, D. M.;
Xu, Y. A Mild Cu(I)-Catalyzed Oxidative Aromatization of Indolines to
Indoles. J. Org. Chem. 2016, 81, 10009−10015. (d) Peng, F.; Chen, Y.;
Chen, C.; Dormer, P. G.; Kassim, A.; McLaughlin, M.; Reamer, R. A.;
Sherer, E. C.; Song, Z. J.; Tan, L.; Tudge, M. T.; Wan, B.; Chung, J. Y. L.
Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor
Omarigliptin. J. Org. Chem. 2017, 82, 9023−9029.
(2) The intermediate for this transformation is styrene, generated in
situ via elimination of water.
(3) (a) Carreno, M. C.; Ruano, J. G.; Toledo, M. A.; Urbano, A. ortho-
̃
Directed metallation in the regiocontrolled synthesis of enantiopure 2-
and/or 3-substituted (S)-(p-tolylsulfinyl)-1,4-benzoquinones. Tetrahe-
dron: Asymmetry 1997, 8, 913−921. (b) Majetich, G.; Zhang, Y.; Tian,
X.; Britton, J. E.; Li, Y.; Phillips, R. Synthesis of ( )- and
(+)-perovskone. Tetrahedron 2011, 67, 10129−10146.
(4) (a) Curzons, A. D.; Mortimer, D. N.; Constable, D. J. C.;
Cunningham, V. L. Green chemistry measures for process research and
(16) It was later discovered that these two steps could be telescoped in
one pot using DABCO as additive, for details, please see Supporting
Information.
́
́
development. Green Chem. 2001, 3, 1−6. (b) Jimenez-Gonzalez, C.;
Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Using the Right Green
G
https://dx.doi.org/10.1021/acs.oprd.0c00241
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
(17) (a) Saikia, I.; Borah, A. J.; Phukan, P. Use of Bromine and Bromo-
Organic Compounds in Organic Synthesis. Chem. Rev. 2016, 116,
6837−7042. (b) Majetich, G.; Hicks, R.; Reister, S. Electrophilic
Aromatic Bromination Using Bromodimethylsulfonium Bromide
Generated in Situ. J. Org. Chem. 1997, 62, 4321−4326. (c) Williams,
A. B.; Weiser, P. T.; Hanson, R. N.; Gunther, J. R.; Katzenellenbogen, J.
A. Synthesis of Biphenyl Proteomimetics as Estrogen Receptor-α
Coactivator Binding Inhibitors. Org. Lett. 2009, 11, 5370−5373.
Ullmann type chemistry: from mechanistic aspects to modern
development. Chem. Soc. Rev. 2014, 43, 3525−3550.
(23) For an allyl protecting group approach, please see: Shishido, K.;
Goto, K.; Miyoshi, S.; Takaishi, Y.; Shibuya, M. Synthetic studies on
diterpenoid quinones with interleukin-1 inhibitory activity. Total
synthesis of ( )- and (+)-triptoquinone A. J. Org. Chem. 1994, 59,
406−414.
(24) Singel crystal X-ray diffraction data clearly indicates hydrogen
bonding present between the hydroxyl group of the bromophenol and
nitrogen of DABCO. For details, please see SI.
̀
(18) Calo, V.; Lopez, L.; Pesce, G.; Ciminale, F.; Todesco, P. E.
Solvent effect on the ortho : para ratio in the bromination of phenols.
Bromination with bromocyclohexadienones and N-bromosuccinimide.
J. Chem. Soc., Perkin Trans. 2 1974, 2, 1189−1191.
(19) Duan, J.; Zhang, L. H.; Dolbier, W. R., Jr. A Convenient New
Method for the Bromination of Deactivated Aromatic Compounds.
Synlett 1999, 1245−1246.
(25) For examples of phenol-amine co-crystals, see: (a) Huang, K.-S.;
Britton, D.; Etter, M. C.; Byrn, S. R. A novel class of phenol−pyridine
co-crystals for second harmonic generation. J. Mater. Chem. 1997, 7,
713−720. (b) Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A.
Two independent C2 (20) chains in the hydrogen-bonded structure of
2
4,4′-biphenol-4,4′-bipyridyl (1/1). Acta. Cryst. 1999, 55, 2133−2136.
(c) Loehlin, J. H.; Etter, M. C.; Gendreau, C.; Cervasio, E. Hydrogen-
Bond Patterns in Several 2:1 Amine-Phenol Cocrystals. Chem. Mater.
1994, 6, 1218−1221. (d) Takama, M.; Yasui, M.; Harada, S.; Kasai, N.;
Tanaka, K.; Toda, F. The Crystal and Molecular Structure of 1 : 2
Molecular Complex of 1,4-Diazabicyclo[3.3.3]octane (DABCO) with
p-Cresol. Bull. Chem. Soc. Jpn. 1988, 61, 567−568.
(20) (a) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M.
Atroposelective Total Synthesis of Axially Chiral Biaryl Natural
Products. Chem. Rev. 2011, 111, 563−639. (b) Lee, Y. E.; Cao, T.;
Torruellas, C.; Kozlowski, M. C. Selective Oxidative Homo- and Cross-
Coupling of Phenols with Aerobic Catalysts. J. Am. Chem. Soc. 2014,
136, 6782−6785. (c) Esguerra, K. V. N.; Fall, Y.; Petitjean, L.; Lumb, J.-
P. Controlling the Catalytic Aerobic Oxidation of Phenols. J. Am. Chem.
Soc. 2014, 136, 7662−7668. (d) Peters, D. S.; Romesberg, F. E.; Baran,
P. S. Scalable Access to Arylomycins via C−H Functionalization Logic.
J. Am. Chem. Soc. 2018, 140, 2072−2075.
́
́
(26) Hernandez Sanchez, F.; Molina Mateo, J.; Romero Colomer, F.
́
́
J.; Salmeron Sanchez, M.; Gomez Ribelles, J. L.; Mano, J. F. Influence of
Low-Temperature Nucleation on the Crystallization Process of Poly(l-
lactide). Biomacromolecules 2005, 6, 3283−3290.
(21) (a) Aalten, H. L.; Van Koten, G.; Grove, D. M.; Kuilman, T.;
Piekstra, O. G.; Hulshof, L. A.; Shelfon, R. A. The copper catalysed
reaction of sodium methoxide with aryl bromides. A mechanistic study
leading to a facile synthesis of anisole derivatives. Tetrahedron 1989, 45,
5565−5578. (b) Carpentier, J.-F.; Castanet, Y.; Brocard, J.; Mortreux,
A.; Petit, F. A novel and convenient method for palladium-catalysed
alkoxycarbonylation of aryl and vinyl halides using HCO2R/NaOR
system. Tetrahedron Lett. 1991, 32, 4705−4708. (c) Huang, J.; Chen,
Y.; Chan, J.; Ronk, M. L.; Larsen, R. D.; Faul, M. M. An Efficient
Copper-Catalyzed Etherification of Aryl Halides. Synlett 2011, 2011,
1419−1422. (d) Zhang, H.; Ma, D.; Cao, W. Synlett 2007, 2007, 243−
246. (e) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Copper-
Catalyzed Coupling of Aryl Iodides with Aliphatic Alcohols. Org. Lett.
2002, 4, 973−976. (f) Altman, R. A.; Shafir, A.; Chio, A.; Lichtor, P. A.;
Buchwald, S. L. An Improved Cu-Based Catalyst System for the
Reactions of Alcohols with Aryl Halides. J. Org. Chem. 2008, 73, 284−
286. (g) Naidu, A. B.; Sekar, G. An efficient intermolecular BINAM−
copper(I) catalyzed Ullmann-type coupling of aryl iodides/bromides
with aliphatic alcohols. Tetrahedron Lett. 2008, 49, 3147−3151.
(h) Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. Copper(I)-Catalyzed
Aryl Bromides To Form Intermolecular and Intramolecular Carbon−
Oxygen Bonds. J. Org. Chem. 2009, 74, 5075−5078. (i) Niu, J.; Zhou,
H.; Li, Z.; Xu, J.; Hu, S. An Efficient Ullmann-Type C−O Bond
Formation Catalyzed by an Air-Stable Copper(I)−Bipyridyl Complex.
J. Org. Chem. 2008, 73, 7814−7817. (j) Schaarschmidt, D.; Lang, H.
Copper(I)-Mediated Synthesis of Ferrocenyl Alkyl Ethers. Organo-
metallics 2010, 29, 4196−4198. (k) Jiang, J.-A.; Chen, C.; Guo, Y.; Liao,
D.-H.; Pan, X.-D.; Ji, Y.-F. A highly efficient approach to vanillin starting
from 4-cresol. Green Chem. 2014, 16, 2807−2815. (l) Xia, S.; Gan, L.;
Wang, K.; Li, Z.; Ma, D. Copper-Catalyzed Hydroxylation of
(Hetero)aryl Halides under Mild Conditions. J. Am. Chem. Soc. 2016,
138, 13493−13496. (m) Whitesides, G. M.; Sadowski, J. S.; Lilburn, J.
Copper(I) alkoxides. Synthesis, reactions, and thermal decompositions.
J. Am. Chem. Soc. 1974, 96, 2829−2835.
(27) For detailed NMR study, please see SI.
(28) (a) Li, J.-H.; Wang, D.-P.; Xie, Y.-X. CuI/Dabco as a highly active
catalytic system for the Heck-type reaction. Tetrahedron Lett. 2005, 46,
4941−4944. (b) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.;
Zhang, M.-B.; Hu, X.-C. CuI-Catalyzed Suzuki−Miyaura and
Sonogashira Cross-Coupling Reactions Using DABCO as Ligand. J.
Org. Chem. 2007, 72, 2053−2057. (c) Li, J.-H.; Wang, D.-P. CuI/
DABCO-Catalyzed Cross-Coupling Reactions of Aryl Halides with
Arylboronic Acids. Eur. J. Org. Chem. 2006, 2006, 2063.
(29) For overall and downstream process: (a) Ren, H.; Maloney, K.
M.; Basu, K.; Di Maso, M. J.; Humphrey, G.; Peng, F.; Desmond, R. A.;
Otte, D. A. L.; Alwedi, E.; Liu, W.; Zhang, S.; Song, S.; Arvary, R. A.;
Zompa, M. A.; Lehnherr, D.; Martin, G. E.; Chang, D.; Mohan, A. E.;
Guzman, F. J.; Jellett, L.; Lee, A. Y.; Spencer, G.; Fisher, E. S.; Naber, J.
R.; Lohani, S.; Ruck, R. T.; Campeau, L.-C. Development of a Green &
Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264)
Part 1: Introduction and Process Org. Process Res. Dev., 2020,
DOI: 10.1021/acs.oprd.0c00248. (b) Basu, K.; Lehnherr, D.; Martin,
G. E.; Desmond, R. A.; Lam, Y.-H.; Peng, F.; Chung, J. Y. L.; Arvary, R.
A.; Zompa, M. A.; Zhang, S.-W.; Liu, J.; Dance, Z. E. X.; Larpent, P.;
Cohen, R. D.; Guzman, F. J.; Rogus, N. J.; Di Maso, M. J.; Ren, H.;
Maloney, K. M. Development of a Green & Sustainable Manufacturing
Process for Gefapixant Citrate (MK-7264) Part 3: Development of a
One-Pot Formylation-Cyclization Sequence to the Diaminopyrimidine
Core. Org. Process Res. Dev. 2020, DOI: 10.1021/acs.oprd.0c00246.
(c) Otte, D. A. L.; Basu, K.; Jellett, L.; Whittington, M.; Spencer, G.;
Burris, M.; Corcoran, E. B.; Stone, K.; Nappi, J.; Arvary, R. A.;
Donoghue, D.; Ren, H.; Maloney, K. M.; Naber, J. R. Development of a
Green & Sustainable Manufacturing Process for Gefapixant Citrate
(MK-7264) Part 4: Formylation-Cyclization as a Flow-Batch Process
Leads to Significant Improvements in Process Mass Intensity (PMI)
and CO Generated versus the Batch-Batch Process. Org. Process Res.
Dev., 2020, DOI: 10.1021/acs.oprd.0c00252. (d) Di Maso, M. J.; Ren,
H.; Zhang, S.-W.; Liu, W.; Desmond, R. A.; Alwedi, E.; Narsimhan, K.;
Kalinin, A.; Larpent, P.; Lee, A. Y.; Ren, S.; Maloney, K. M.
Development of a Green & Sustainable Manufacturing Process for
Gefapixant Citrate (MK-7264) Part 5: Completion of the API Free
Base via a Direct Chlorosulfonylation Process. Org. Process Res. Dev.,
2020, DOI: 10.1021/acs.oprd.0c00247. (e) Maloney, K. M.; Zhang, S.-
W.; Mohan, A. E.; Larpent, P.; Ren, H.; Desmond, R.; DiBenedetto, M.;
Liu, W.; Humphrey, G. R.; Lee, I. H.; Sirota, E.; Di Maso, M. J.; Alwedi,
E.; Lee, A. Y.; Song, S.; Chang, H. Y. D. Development of a Green &
Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264)
(22) (a) Klapars, A.; Huang, X.; Buchwald, S. L. A General and
Efficient Copper Catalyst for the Amidation of Aryl Halides. J. Am.
Chem. Soc. 2002, 124, 7421−7428. (b) Buck, E.; Song, Z. J.; Tschaen,
D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Ullmann Diaryl Ether
Synthesis: Rate Acceleration by 2,2,6,6-Tetramethylheptane-3,5-dione.
Org. Lett. 2002, 4, 1623−1626. (c) Nordmann, G.; Buchwald, S. L. A
Domino Copper-Catalyzed C−O Coupling−Claisen Rearrangement
Process. J. Am. Chem. Soc. 2003, 125, 4978−4979. L5: (d) Sambiagio,
C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Copper catalysed
H
https://dx.doi.org/10.1021/acs.oprd.0c00241
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Organic Process Research & Development
pubs.acs.org/OPRD
Article
Part 6: Development of an Improved Commercial Salt Formation
Process. Org. Process Res. Dev., 2020, DOI: 10.1021/acs.oprd.0c00260.
(30) Lee, I. H. Use of Lecithin As an Antistatic Agent in
Nonconductive Crystallization Slurries for Isolating Pure Active
Pharmaceutical Ingredients. Org. Process Res. Dev. 2013, 17, 1330−
1334.
I
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