Development of a green and sustainable manufacturing process for gefapixant citrate (MK-7264). Part 5: Completion of the api free base via a direct chlorosulfonylation process

Article abstract of DOI:10.1021/acs.oprd.0c00247

A scalable two-pot sulfonamidation through the process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. Direct conversion of t

Full text of DOI:10.1021/acs.oprd.0c00247

pubs.acs.org/OPRD
Article
Development of a Green and Sustainable Manufacturing Process for
Gefapixant Citrate (MK-7264). Part 5: Completion of the API Free
Base via a Direct Chlorosulfonylation Process
Michael J. Di Maso,* Hong Ren,* Si-Wei Zhang, Wenjun Liu, Richard Desmond, Embarek Alwedi,
Karthik Narsimhan, Alexei Kalinin, Patrick Larpent, Alfred Y. Lee, Sumei Ren, and Kevin M. Maloney
Cite This: https://dx.doi.org/10.1021/acs.oprd.0c00247
Read Online
Metrics & More
Article Recommendations
ACCESS
ABSTRACT: A scalable two-pot sulfonamidation through the process has been developed for the synthesis of gefapixant citrate, a
P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. Direct
conversion of the diaryl ether precursor to a sulfonyl chloride intermediate using chlorosulfonic acid, followed by treatment with
aqueous ammonia hydroxide, provided the desired sulfonamide in high yield. A pH-swing crystallization allowed for the formation of
a transient acetonitrile solvate that enables the rejection of two impurities. After drying, the desired anhydrous free base form was
isolated in high yield and purity.
KEYWORDS: electrophilic aromatic substitution, sulfonamide, transient solvate, pH-swing crystallization
fter successfully developing a streamlined synthesis of the
synthesis of carbon-14 radiolabeled 3 to support drug
metabolism and pharmacokinetic studies, environmental fate
studies, and human ADME study (absorption, distribution,
metabolism, and excretion). Crucially, this route reduced the
number of steps with radiolabeled intermediates required to
synthesize 14C-3 from four to two while increasing the overall
yield. Unfortunately, while this one-step direct sulfonamidation
reaction enabled radiolabeling studies, the reaction exhibited
several limitations that rendered it unsuitable for use in a
commercial manufacturing process. First, the reaction required
the use of a chlorinated solvent, which is unattractive from a
green chemistry standpoint. In addition, there are safety and
handling concerns for sulfamoyl chloride itself as well as the
superstoichiometic amounts of aluminum trichloride that are
required, as both are highly reactive water-sensitive solids.
In view of the limitations of direct sulfonamidation, we set
our sights on developing an efficient two-step protocol for this
reaction. We therefore turned our attention to investigating the
direct formation of the sulfonyl chloride 6 from arene 1 as this
intermediate could easily be transformed into the desired
sulfonamide 3 (Table 1). Although direct chlorosulfonylation
can be accomplished with chlorosulfonic acid, this reagent
typically forms sulfonic acids as the major products in many
cases,5−9 and the addition of a secondary chlorinating reagent
(e.g., POCl3) or the use of solvent quantities of the reagent are
A
diaminopyrimidine 1,1,2 we turned our attention to
completing the synthesis of gefapixant through the installation
of the sulfonamide functionality to give the API free base 3.
Unfortunately, the first-generation supply route protocol for
this transformation suffered from several deficiencies that
would preclude its use in a commercial route (Scheme 1A):
(1) the synthetic sequence required three distinct chemical
steps to install the sulfonamide; (2) the use of sulfolane, a
Class 2 solvent with strict residual limits (<160 ppm),3 was
undesirable in the final steps of the synthesis; (3) the use of
two highly toxic and hazardous chemicals, chlorosulfonic acid
(HSO3Cl) and POCl3, was likewise unattractive; (4) issues
with process robustness were observed on scale-up; and (5)
multiple recrystallizations of the free base product were
required to reach the purity specifications with respect to
impurities 4, 5, and unidentified phosphate oligomers. Given
the severity of these concerns, we set out to develop a one-step
synthesis of the API that would address these issues and exceed
our standards for a manufacturing route.4
Our studies began with a search for a one-step
sulfonamidation reaction using various sulfur electrophiles
(Scheme 2A). While the use of all of the reagents led to the
formation of the desired C−S bond, the terminal functional
group typically varied between the sulfonic acid and sulfonyl
chloride with little of the desired sulfonamide formed.
Interestingly, while using sulfamoyl chloride as the sulfonylat-
ing reagent, divergent reactivity, depending on whether a
Brønsted or Lewis acid promoter was used, was observed.
While employment of Brønsted acids predominantly afforded
sulfonyl chloride 6, upon switching instead to a Lewis acid, the
same conditions provided the desired sulfonamide 3
exclusively. These conditions proved essential for the efficient
Received: May 22, 2020
https://dx.doi.org/10.1021/acs.oprd.0c00247
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Organic Process Research & Development
pubs.acs.org/OPRD
Article
determine the reason for the effectiveness of this solvent. In
line with the stated goals for our manufacturing process, this
new method allows us to access sulfonyl chloride 6 directly
from arene 1, without the need to first form acid 2 in a separate
step, and also eliminates the use of sulfolane and POCl3.
In addition to the desired product 3, varying levels of two
impurities were observed from the sulfonylation step after the
reaction was quenched with ammonium hydroxide (Table 2).
These impurities were identified as chlorinated arene 9 and
sulfinic acid 10, suggesting the presence of sulfuryl chloride, a
well-known chlorinating reagent,19−23 in the batch of
chlorosulfonic acid employed. Consistent with this hypothesis,
the amounts of these impurities were found to depend on the
batch of chlorosulfonic acid used (entries 1 and 2), and a
significant increase in the quantity of both was observed upon
the addition of one equivalent of sulfuryl chloride to the
chlorosulfonic acid (entry 3). To control the formation of
these impurities, 1,3-dimethoxybenzene (DMB) could be
added to the reaction to scavenge the sulfuryl chloride
(entry 4). For translation to the manufacturing process, an
analytical method has been developed to quantify sulfuryl
chloride levels in chlorosulfonic acid to ensure optimal reagent
quality.24
Scheme 1. (A) First-Generation Route to Provide
Gefapixant Free Base. (B) Poorly Rejecting Impurities
Arising from the First-Generation Sulfonamide Chemistry
With a process to form the sulfonyl chloride 6 in hand, we
turned our attention to optimizing the sulfonamide formation
(Table 3). In the supply process, this conversion was
accomplished by quenching the stream of sulfonyl chloride
into a methanolic solution of ammonia. However, this process
led to methylated impurity 5 that was difficult to purge via
crystallization (Scheme 1B). Alternatively, it was discovered
that the desired sulfonamide 3 could be formed by quenching
the solution of sulfonyl chloride 6 into an aqueous ammonium
hydroxide solution, thereby eliminating the formation of
methylated impurity 5. Further investigation showed that
higher temperatures during quenching led to an increased rate
of hydrolysis of sulfonyl chloride 6 and the corresponding
formation of increasing levels of the sulfonic acid 2, which was
attributed to the evaporation of ammonia from the solution. As
mitigation, the addition was performed at an internal
temperature of 0−15 °C, which enabled us to keep the
sulfonic acid impurity levels below 2.0 LCAP.25
The sulfonamide precipitates from the solution during this
quench procedure. Unfortunately, the direct isolation of this
solid led to a low-weight-percent solid that contained up to 4−
5% of the acetylated byproduct 8 (Table 4). While attempts to
hydrolyze this impurity with the addition of exogenous amines
were unsuccessful, the addition of aqueous sodium hydroxide
served to hydrolyze the impurity to the API free base, resulting
in a concomitant increase in the yield of the reaction. Of
additional benefit, the existing solids underwent dissolution
during the process and provided the opportunity to develop a
controlled crystallization of the product and increase the purity
of the isolated free base 3.
needed to effect the selective transformation to the sulfonyl
chloride.10−16 Keen to minimize the amount of chlorosulfonic
acid used and eliminate the use of a second hazardous reagent
in this step, we screened the effect of solvent on the
chlorosulfonation reaction to identify conditions for an
efficient chlorosulfonylation using chlorosulfonic acid alone
(Table 1). As expected, the use of three equivalents of
chlorosulfonic acid, in a series of solvents, provided varying
levels of conversion to the undesired sulfonic acid 2. Although
sulfolane, which was used in the supply route, gave almost
exclusively the undesired acid 2, we were pleased to find that,
in acetonitrile, a 7:3 mixture of the sulfonic acid 2 and sulfonyl
chloride 6 was formed.17,18 Increasing the stoichiometry of
chlorosulfonic acid from 3 to 5 equivalents provided almost
complete selectivity for the sulfonyl chloride over the sulfonic
acid. Time-course experiments later demonstrated that, under
these conditions, pyrimidine 1 is initially converted to sulfonic
acid 2; upon aging at 45 °C for 16 h, acid 2 is then converted
to the desired sulfonyl chloride 6. Additionally, acetamide was
observed by GC analysis of the mixture, along with 4−5% of
acetylated product 8 (vide infra). This observation indicates
that acid-promoted hydrolysis of acetonitrile occurs, which
may be important to drive the reaction to the desired sulfonyl
chloride by consuming water; further studies on the
sulfonylation mechanism are ongoing in our laboratory to
To develop this crystallization, the solubility of sulfonamide
3 was studied as a function of pH (Figure 1). As expected, this
compound is highly soluble under basic conditions owing to
the deprotonation of the sulfonamide to form the correspond-
ing sodium salt. As a result, we envisioned that the preferred
procedure would entail the slow addition of acid to this basic
solution to afford the neutral API in a reactive crystallization.
Citric acid was chosen as the acid to minimize the risk of
forming any other potential salts (as the final API form is the
gefapixant citrate salt). From the solubility curve, seeding in
B
https://dx.doi.org/10.1021/acs.oprd.0c00247
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
Scheme 2. (A) High-Throughput Screen of a One-Pot Sulfonamidation Reaction. (B) Differential Selectivity with Brønsted or
Lewis Acids and Sulfamoyl Chloride. (C) Application of Lewis Acid Conditions to the Synthesis of 14C-3
Table 1. Effect of Solvent on Ratio of Sulfonic Acid 2 to
Desired Sulfonyl Chloride 6.
This observation raised the question of the form of the API
throughout the entire crystallization process (Table 5). When
the impurities are rejected, a seedbed of anhydrous form 1
grows before turning over to an acetonitrile solvate, and this
solvate continues to crystallize from the solution throughout
the pH swing. During the washing of the wet cake with water,
the solids desolvate to provide the desired anhydrous form 1 of
the API in the dry cake. At our original solvent composition
(∼14% MeCN/Water), form 1 and the acetonitrile solvate
were both stable and turnover to the acetonitrile solvate was
slow. The addition of two volumes of acetonitrile (20%
MeCN/Water) biased the system toward the acetonitrile
solvate and allowed for fast form turnover with concomitantly
improved impurity rejection.27
To develop a successful thermodynamic crystallization, a
study of the relative stabilities of the two forms in mixtures of
acetonitrile and water was undertaken (Figure 2). Maintaining
the acetonitrile level above 15% ensures that the acetonitrile
solvate is thermodynamically preferred. While seeding with the
acetonitrile solvate allows for the immediate growth of the
acetonitrile solvate, desolvation of the seed on standing
required additional processing to provide acetonitrile solvate.
Therefore, seeding with form 1 was preferred due to the facile
turnover to the transient solvate under the crystallization
conditions, as well as the ease of storing the form 1 seed. This
unexpected discovery of a transient acetonitrile solvate allowed
for consistent impurity rejection while enabling isolation of the
desired form of the product in high yield and purity was a key
breakthrough in the development of this sulfonamidation
process.
entry
solvent
equiv HSO3Cl
conversion
ratio 2:6
1
2
3
4
sulfolane
DMAc
DMSO
NMP
MeCN
MeCN
MeCN
MeCN
3
3
3
3
3
3
4
5
100
<5
<5
98:2
nd
nd
<5
nd
a
5
100
100
100
100
30:70
30:70
6:94
1.6:98.4
a
5
6
b
b
7
a
b
Reaction aged for 3 h. Reaction aged 16−18 h at 45 °C. nd = not
determined.
the range of pH 12.7−13.0 was suitable to grow a seedbed
before adjusting the pH to 10.8−11.3 for isolation. Adjusting
the pH further failed to offer a significant improvement in the
mother liquor losses.
While this crystallization procedure allowed for excellent
rejection of several impurities, two problematic impurities were
not consistently rejected under the same conditions or in the
final citrate salt formation.26 However, it was observed that the
addition of two volumes of acetonitrile to the crystallization
stream allowed for the isolation of the desired crystal form in
increased purity with diminished amounts of these species.
C
https://dx.doi.org/10.1021/acs.oprd.0c00247
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
Table 2. Formation of Impurities Chloroarene 9 and Sulfinic Acid 10 During Sulfonylation with Sulfuryl Chloride
entry
conditions
3 (LCAP)
9 (LCAP)
10 (LCAP)
1
2
3
4
99% HSO3Cl (supplier A)
97% HSO3Cl (supplier B)
99% HSO3Cl + 1 equiv SO2Cl2
97% HSO3Cl + 20 mol % DMB
93.0
80.6
32
0.2
4.1
22
0.2
3.7
21
2.3
93.0
0.92
transient acetonitrile solvate, allows for single, direct isolation
of the API in excellent purity and greatly increased yield. These
combined improvements result in a vastly improved isolation
procedure that eliminates the tedious multiple recrystalliza-
tions required in the first-generation process, resulting in a 42%
reduction in the amount of waste generated in the sulfonamide
installation. Indeed, the overall PMI for the new process from
arene 1 to sulfonamide 3 is now lower than the PMI of a single
one of the multiple recrystallizations of product 3 that were
originally required. The new process has been transferred to
our scale-up facilities and successfully demonstrated on up to
440 kg scale with a 90−94% yield and >98.5% purity of
gefapixant free base.
Table 3. Temperature Screening for the Reverse Quench of
Sulfonyl Chloride 6.
entry
temperature (°C)
3 (LCAP)
2 (LCAP)
1
2
3
0
15
30
89.9
87.0
82.5
1.0
5.4
11.3
EXPERIMENTAL SECTION
CONCLUSIONS
■
■
Preparation of Gefapixant Free Base Form 1 (3). To a
suspension of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-
2,4-diamine (47.0 kg, 171 mol) in 141 L of acetonitrile at −10
°C was added chlorosulfonic acid (63.1 L, 942 mol) while
maintaining the internal temperature below 25 °C. The
solution was aged for 1 h at 25 °C and then heated to 45
°C for 12 h. The solution was allowed to cool to 20 °C and
added to a solution of 235 L ammonium hydroxide and 71 L of
acetonitrile at −10 °C while maintaining the internal
temperature below 15 °C. The slurry was aged at 10 °C for
1 h, heated to 25 °C, and aged for 1 h. The slurry was diluted
with 560 L of water and 190 L of 50 wt % sodium hydroxide to
provide a homogeneous solution that was heated to 35 °C for
2 h. The solution was allowed to cool to 22 °C and the pH of
the solution was adjusted to 12.9 with a 2 M aqueous solution
of citric acid. The solution was seeded with gefapixant free base
The new sulfonamidation process significantly improves on all
aspects of the supply route (Scheme 3). Careful solvent
selection in the chlorosulfonylation reaction allowed for the
elimination of sulfolane and POCl3. These changes provide a
greener and operationally simpler process, while also
preventing the formation of a dimeric impurity resulting
from the reaction of sulfonamide 3 with phosphorus
oxychloride. While the highly corrosive chlorosulfonic acid
remains an important reagent in the new process, engineering
controls have been put in place to handle the reagent safely on
scale.28 By setting purity specifications for the chlorosulfonic
acid, it is now possible to prevent the formation of several
impurities generated from the dissolved sulfuryl chloride that
can be present in this reagent. Additional impurity control
resulting from the new quench procedure, along with the
controlled pH-swing crystallization and the discovery of a
Table 4. Hydrolysis of an Acetylated Byproduct and Slurry Dissolution
entry
conditions
outcome
1
2
3
1,2-ethylenediamine, 50 °C
1,2-ethanolamine
NaOH, H2O, 40 °C
no change
no change
slurry dissolves, complete hydrolysis in 2 h
D
https://dx.doi.org/10.1021/acs.oprd.0c00247
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
Figure 1. Solubility of sulfonamide 3 in the reaction solvent based on solution pH. pH was adjusted using a 2 M aqueous citric acid solution.
Table 5. Crystal Form Studies for the Isolation of API Free Base 3
solvent composition
<15% MeCN
>15% MeCN
<15% MeCN
>15% MeCN
seed form
slurry form
dry cake form
impurities (LCAP)
form 1
form 1
form 1
0.20, 0.21
form 1
MeCN solvate
form 1
MeCN solvate
form 1
form 1
MeCN solvate
MeCN solvate
form 1
0.04, 0.02
0.20, 0.21
0.04, 0.02
6.37 (s, 2H), 5.85 (s, 2H), 3.89 (s, 3H), 3.41 (hept, J = 6.6 Hz,
1H), 1.27 (d, J = 6.8 Hz, 6H).
14C-labeled-1. To a solution of 2-(2-isopropyl-4-methoxy-
phenoxy)-3-phenylamino-acrylonitrile (7)29 (805 mg, 2.61
mmol, 1.5 equiv) in anhydrous DMSO (5.6 mL, 7 V) was
added [14C]-guanidine hydrochloride (170 mg, 1.74 mmol, 1.0
equiv, 100 mCi), followed by potassium t-butoxide (215 mg,
1.91 mmol, 1.1 equiv) at 22 °C. The mixture was stirred at 120
°C for 28 h and then allowed to cool to 22 °C. The mixture
was partitioned between EtOAc and water. The organic layer
was separated, dried over sodium sulfate, and evaporated. The
crude product was applied to a silica gel column, eluting with
DCM/MeOH/Et3N = 100:1:1 to afford the desired product
14C-1 (46 mCi; RCP > 98%, 46.0% radiochemical yield
(RCY)).
Figure 2. Thermodynamic stability of the acetonitrile solvate 1 and
form 1 crystal forms of API free base 3 with respect to temperature
and solvent concentration (V/V% water/acetonitrile).
(470 g, 1.19 mol) aged for 2 h, acidified to pH 10.5−11.3 with
a 2 M aqueous solution of citric acid over 5−10 h, and then
aged for 2 h. The slurry was filtered, the resulting cake was
washed with 9:1 water:acetonitrile (2 × 118 L) and water (2 ×
235 L) and dried at 55 °C under vacuum to provide gefapixant
1
free base 3 (50.9 kg, 91%) as a solid. H NMR (500 MHz,
DMSO-d6) δ 7.36 (s, 1H), 7.07 (s, 1H), 7.05−6.89 (m, 3H),
Scheme 3. Safe, Scalable, and Green Manufacturing Route to Gefapixant Free Base 3
E
https://dx.doi.org/10.1021/acs.oprd.0c00247
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
14C-labeled-3. To a solution of 14C-1 (46 mCi, ∼0.8 mmol)
and sulfamoyl chloride (414 mg, 3.6 mmol) in anhydrous DCE
(6 ml) was added AlCl3 (426 mg, 3.2 mmol) at 20 °C. The
mixture was stirred at 50 °C overnight (17 h) under nitrogen.
The reaction mixture was quenched with 5% aq. citric acid
solution and then purified by high-performance liquid
chromatography (HPLC). The fractions containing the desired
product (radiochemical purity (RCP) > 99%, chemical purity
(CP) > 99%) were pooled and evaporated under reduced
pressure to yield 21.0 mCi of the product as off-white solid
(RCP > 99%, CP > 99%, 45.6% RCY) as a TFA salt. The
specific activity was determined to be 58.4 mCi/mmol by MS
analysis.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Francois Levesque, Kallol Basu,
Rebecca Ruck, Guy R. Humphrey, and Christopher Nawrat
(all at Merck & Co., Inc.) for providing insightful feedback on
the manuscript.
ABBREVIATIONS USED
■
LCAP=liquid chromatography area percent
RCY=radiochemical yield
REFERENCES
■
AUTHOR INFORMATION
■
(1) 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.
(2) 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.
(3) ICH Q3C Impurities: Guideline for Residual Solvents (R6).
https://database.ich.org/sites/default/files/Q3C-R6_Guideline_
ErrorCorrection_2019_0410_0.pdf (accessed Nov 26, 2019).
(4) 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 Manufactur-
ing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction
and Process Overview. Org. Process Res. Dev. 2020, DOI: 10.1021/
acs.oprd.0c00248.
(5) Al-Ansary, G. H.; Ismail, M. A. H.; Abou El Ella, D. A.; Eid, S.;
Abouzid, K. A. M. Molecular design and synthesis of HCV inhibitors
based on thiazolone scaffold. Eur. J. Med. Chem. 2013, 68, 19−32.
(6) Jiang, H.; Xu, J.; Xiao, G.; Cui, Z. Method for preparing sodium
m-nitrobenzene sulfonate or its derivative via sulfonating with
chlorosulfonic acid, CN108997175A, 2018.
(7) Li, Z.; Wang, L. Silica-supported benzenesulfonic acid catalyzed
Claisen rearrangement of allyl aryl ethers. Xibei Shifan Daxue Xuebao,
Ziran Kexueban 2010, 46, 59−63.
(8) Ma, D.; Pan, Q.; Pan, S. Process for preparation of rivastigmine
and tartrate. WO2007025481A1, 2007.
(9) Santos, M. A.; Marques, S. M.; Tuccinardi, T.; Carelli, P.;
Panelli, L.; Rossello, A. Design, synthesis and molecular modeling
study of iminodiacetyl monohydroxamic acid derivatives as MMP
inhibitors. Bioorg. Med. Chem. 2006, 14, 7539−7550.
(10) Prabhakaran, P. C.; Sharma, A.; Gorman, C. Chlorosulfonic
Acid. In Encyclopedia of Reagents for Organic Synthesis, 2008.
(11) Geoghegan, K.; Smullen, S.; Evans, P. Halonium Ion Triggered
Rearrangement of Unsaturated Benzo-Annulated Bi- and Tricyclic
Sulfonamides. J. Org. Chem. 2013, 78, 10443−10451.
Corresponding Authors
Michael J. Di Maso − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0003-1262-6126;
Email: mike.dimaso@merck.com
Hong Ren − Department of Process Research and Development,
Merck & Co., Inc., Rahway, New Jersey 07065, United States;
orcid.org/0000-0002-0754-7282; Email: hong.ren@
merck.com
Authors
Si-Wei Zhang − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0001-8677-3722
Wenjun Liu − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Richard Desmond − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Embarek Alwedi − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0002-7031-2427
Karthik Narsimhan − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Alexei Kalinin − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Patrick Larpent − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Alfred Y. Lee − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0003-3684-4101
Sumei Ren − Department of Process Research and Development,
Merck & Co., Inc., Rahway, New Jersey 07065, United States
Kevin M. Maloney − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0003-1422-5422
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00247
(12) Li, W.; Li, J.; Wu, Y.; Wu, J.; Hotchandani, R.; Cunningham,
K.; McFadyen, I.; Bard, J.; Morgan, P.; Schlerman, F.; Xu, X.; Tam, S.;
Goldman, S. J.; Williams, C.; Sypek, J.; Mansour, T. S. A Selective
Matrix Metalloprotease 12 Inhibitor for Potential Treatment of
Chronic Obstructive Pulmonary Disease (COPD): Discovery of (S)-
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
F
https://dx.doi.org/10.1021/acs.oprd.0c00247
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
2-(8-(Methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-
methylbutanoic acid (MMP408). J. Med. Chem. 2009, 52, 1799−
1802.
(13) Petroff, J. T.; Skubic, K. N.; Arnatt, C. K.; McCulla, R. D.
Asymmetric Dibenzothiophene Sulfones as Fluorescent Nuclear
Stains. J. Org. Chem. 2018, 83, 14063−14068.
(14) Ricouart, A.; Gesquiere, J. C.; Tartar, A.; Sergheraert, C. Design
of potent protein kinases inhibitors using the bisubstrate approach. J.
Med. Chem. 1991, 34, 73−8.
(15) Roemmele, R. C.; Rapoport, H. Removal of N-arylsulfonyl
groups from hydroxy α-amino acids. J. Org. Chem. 1988, 53, 2367−71.
(16) Singh, R.; Bordeaux, M.; Fasan, R. P450-Catalyzed Intra-
molecular sp3 C-H Amination with Arylsulfonyl Azide Substrates.
ACS Catal. 2014, 4, 546−552.
̈
(17) Janosik, T.; Shirani, H.; Wahlstrom, N.; Malky, I.; Stensland, B.;
Bergman, J. Efficient sulfonation of 1-phenylsulfonyl-1H-pyrroles and
1-phenylsulfonyl-1H-indoles using chlorosulfonic acid in acetonitrile.
Tetrahedron 2006, 62, 1699−1707.
(18) This addition is highly exothermic (ΔTad = 109 °C). The
addition is performed while maintaining the internal temperature of
the reaction below 10 °C.
(19) Maynard, G. D. Sulfuryl Chloride. In Encyclopedia of Reagents
for Organic Synthesis, 2001.
(20) Gnaim, J. M.; Sheldon, R. A. Highly regioselective ortho-
chlorination of phenol with sulfuryl chloride in the presence of
amines. Tetrahedron Lett. 1995, 36, 3893−6.
(21) Hojo, M.; Masuda, R. Electrophilic chlorination by sulfuryl
chloride in the presence of silica gel. Synth. Commun. 1975, 5, 169−
71.
(22) Kinsinger, T.; Kazmaier, U. C-H functionalization of N-
methylated amino acids and peptides as tool in natural product
synthesis: Synthesis of Abyssenine A and Mucronine E. Org. Lett.
2018, 20, 7726−7730.
(23) Watson, W. D. Regioselective para-chlorination of activated
aromatic compounds. J. Org. Chem. 1985, 50, 2145−2148.
(24) The details and analytical method are to follow in a subsequent
publication.
(25) In our efforts to scale this new method to the 20−50 gram
scale, we found that the quenched product formed a gummy solid
during the beginning of the quench before forming a well dispersed
slurry. This behavior was flagged as a risk to damage the agitator on
scale up to the pilot plant. We found that the addition of two volumes
of acetonitirile to the quench media allowed for the addition of
sulfonyl chloride stream without the formation of gummy material.
(26) Please insert citation for the following manuscript in this series
of papers.
(27) We posited that the addition of other solvents to our
crystallization may allow for the isolation of an alternative solvate of
the API that we could isolate while rejecting these impurities. The
addition of 1−2 volumes of several solvents did lead to an increase in
the rejection of these impurities; however, we were unwilling to risk
taking new solvates into our final crystallization step.
(28) Additionally, the use of this reagent avoids longer alternative
routes that would require installation of a halogen to allow for
transition metal catalyzed formation of the sulfonamide. Due to the
chelating nature of the diaminopurine, we did not believe there was a
high probability of success in removing transition metals from the
API, especially this late in the synthesis.
(29) Dvorak, C. A.; Green, K. L.; Lee, G. R. Process for synthesis of
phenoxy diaminopyrimidine derivatives. U.S. Patent
US8,003,7882011.
G
https://dx.doi.org/10.1021/acs.oprd.0c00247
Org. Process Res. Dev. XXXX, XXX, XXX−XXX