Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib

Article abstract of DOI:10.1021/acs.oprd.0c00366

The development of a commercial route toward the JAK1 inhibitor abrocitinib is described. The application of a late-stage Lossen rearrangement provided the desired cis-diaminocyclobutane, which was subsequently sulfonylated using a novel water-tolerable triazole sulfonylating reagent to provide the active pharmaceutical ingredient.

Full text of DOI:10.1021/acs.oprd.0c00366

pubs.acs.org/OPRD
Communication
Development of a Nitrene-Type Rearrangement for the Commercial
Route of the JAK1 Inhibitor Abrocitinib
Christina G. Connor, Jacob C. DeForest, Phil Dietrich, Nga M. Do,* Kevin M. Doyle, Shane Eisenbeis,
Elizabeth Greenberg, Sarah H. Griffin, Brian P. Jones, Kris N. Jones, Michael Karmilowicz, Rajesh Kumar,
Chad A. Lewis,* Emma L. McInturff, J. Christopher McWilliams, Ruchi Mehta, Bao D. Nguyen,
Anil M. Rane, Brian Samas, Barbara J. Sitter, Howard W. Ward, and Mark E. Webster
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ABSTRACT: The development of a commercial route toward the JAK1 inhibitor abrocitinib is described. The application of a late-
stage Lossen rearrangement provided the desired cis-diaminocyclobutane, which was subsequently sulfonylated using a novel water-
tolerable triazole sulfonylating reagent to provide the active pharmaceutical ingredient.
KEYWORDS: process chemistry, Curtius rearrangement, Lossen rearrangement, biocatalysis, JAK inhibitor, Pfizer
INTRODUCTION
■
The Janus kinase family of intracellular tyrosine kinases
consists of four members: JAK1, JAK2, JAK3, and TYK2.
JAK inhibitors have demonstrated therapeutic potential for the
treatment of autoimmune disorders and hematological
malignancies through signaling mediation of various cytokines
and growth factors.1−5 The U.S. Food and Drug Admin-
istration (FDA)-approved JAK inhibitors include tofacitinib
(Pfizer),6 baricitinib (Eli Lilly/Incyte),7 ruxolitinib (Incyte),8
and upadacitinib (AbbVie).9 A large number of other JAK
inhibitors are currently in various clinical trials. Pfizer’s JAK1
inhibitor, abrocitinib (1),10 was granted Breakthrough Therapy
designation by the FDA for moderate to severe atopic
Figure 1. Retrosynthesis of abrocitinib (1).
dermatitis in February 2018. Advancement of 1 to phase 3
clinical trials and preparation for commercial launch has
spurred the development of a safe and efficient manufacturing
route.
a post fragment union amination. Both strategies would utilize
a high-energy nitrene-type rearrangement to install one or both
amine functionalities from a simple carboxylate precursor 3.
Choosing the appropriate rearrangement from a safety and
scalability perspective became the primary driver guiding the
commercial route selection.
The enabling route utilized a Curtius approach to build
diaminocyclobutane 10 (Scheme 1). Readily available cyclo-
butanone-3-carboxylic acid (3) was exposed to diphenylphos-
phoryl azide (DPPA) in the presence of triethylamine to form
acyl azide intermediate 4. Heating the acyl azide resulted in the
nitrene rearrangement to give isocyanate 5, which was trapped
with benzyl alcohol to afford benzyl carbamate 6.
RESULTS AND DISCUSSION
■
Two strategies were evaluated for 1, as shown in Figure 1: (A)
addition of a diaminocyclobutane to 4-chloropyrrolopyrimi-
dine 2 and (B) addition of a monoaminocyclobutane to 2 with
a subsequent amination. Access to the cis-1,3-diaminocyclo-
butane would be a key challenge to either strategy. Current
methods to synthesize 1,3-diamino-substituted cyclobutanes
remain limited to [2 + 2] cycloaddition,11 reductive
amination,10,12 amination of halides/sulfonates, and func-
tional-group rearrangements.10,13 Some challenges to the
manufacture of low-molecular-weight diamines include pH-
dependent solubility, volatility, and difficult reaction analytics.
While route A offers higher convergence, it requires the
synthesis of a fully functionalized diaminocyclobutane.
Introduction of the pyrrolopyrimidine core earlier in the
synthetic route (route B) may convey better physical
properties, such as solubility and/or crystallinity, but requires
Special Issue: Celebrating Women in Process Chem-
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Received: August 12, 2020
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© XXXX American Chemical Society
A

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Scheme 1. Curtius Rearrangement to Access cis-Diamine 10
Scheme 2. Completion of the Synthesis of API 1
Scheme 3. Alternative Nitrene Rearrangement Approaches
ReactIR studies detected a buildup of 4 prior to heating and
rearrangement to form 5, which occurred when the solution
was warmed beyond 50 °C. The most reproducible method for
this reaction was to add DPPA to a preheated solution of the
acid at 55 °C, which showed little to no buildup of the acyl
azide. Yield loss in this process occurred by known degradative
pathways,14 including the formation of carbamate 7 and
volatile cyclobutenone 8 from 6 and the subsequent reaction of
7 and 5 to form urea byproduct 9. Extensive optimization of
this reaction, including an evaluation of flow processing, did
not improve the yields or achieve better control of byproduct
formation. To convert 6 to 10, a cryogenic reductive amination
provided an approximately 4:1 ratio of diastereomers in favor
of the desired cis isomer 10. Isolation as the hydrochloride salt
and successive recrystallizations improved the diastereomeric
ratio to >99:1. Despite these challenges, the Curtius approach
(Scheme 1) was scaled successfully to supply >600 kg of 6 for
early clinical studies. However, because of the significant safety
risk associated with the potential buildup of 4, the batch size
was limited on scale (∼60 kg of 3). The batch size limitation
and yield loss due to degradation of highly reactive
intermediates called for an alternative method to access the
diaminocyclobutane for commercial-scale manufacture.
dihydrobromide salt of the tosyl core in 2-MeTHF with
triethylamine followed by the addition of propane-1-sulfonyl
chloride (14) provided the tosyl-protected API. Hydrolysis
using NaOH followed by pH adjustment crystallized the API.
The enabling route was able to produce several hundred
kilograms of the API to support early clinical trials for the
program while a commercial route was being developed.
As an alternative approach, we chose to evaluate the nitrene
chemistry on the cyclobutylamine−pyrrolopyrimidine core
structure. The increased molecular size of the heterocyclic core
could improve the physical properties and ease of handing of
intermediates as well as simplify the reaction analytics.
The Hofmann rearrangement has been used on a multikilo-
gram scale15−17 and was investigated as an alternative to the
Curtius rearrangement (Scheme 3A). Incompatibility of the IIII
oxidant with the electron-rich pyrrolopyrimidine required
prudent selection of reagents, protecting group strategies,
and reaction conditions. The aminocyclobutylamide was
screened under typical conditions for a Hofmann rearrange-
ment. A blend of PhI(OAc)2 in DMF, THF, and water was
found to be effective for the reaction. After treatment with HBr
in acetic acid, dihydrobromide salt 13 was isolated in a modest
58% yield. Protection of the pyrrolo nitrogen was found to be
critical to the success of the rearrangement, as otherwise rapid
oxidative degradation was observed. While this route was
viable, we did not pursue this approach because of the
increased process mass intensity18 resulting from the required
use of protecting groups.19
To complete the active pharmaceutical ingredient (API), the
stereoenriched cyclobutyldiamine 10 was reacted with tosyl-
protected 4-chloropyrrolopyrimidine 11 in isopropyl alcohol
(IPA) with diisopropylethylamine (DIPEA) (Scheme 2).
Intermediate 12 was then treated with hydrobromic acid to
deprotect the benzyl carbamate and afford the penultimate
amine dihydrobromide salt 13 as a solid. Slurrying the
Compared with the Curtius and Hofmann rearrangements,
the Lossen reaction requires less reactive reagents to form the
B
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Scheme 4. Commercial Route to Abrocitinib (1)
nitrene-type intermediate because of the “pre-installed”
oxidation state of the nitrogen, which is introduced as a
hydroxamic acid (16 in Scheme 3B). The reagents typically
employed are dehydrative and would be more compatible with
the unprotected pyrrolopyrimidine. We elected to test the
Lossen reaction on the advanced intermediate 16, encouraged
by results from Bristol-Myers-Squibb on the reaction of a
steroid-derived hydroxamic acid to give a tertiary amine.20
Isopropyl ester 18 was identified as the ideal starting
material for balancing a facile approach to the hydroxamic acid,
stability of the subsequent amino ester during processing, and
ease of handling the free-flowing liquid (Scheme 4).21 Ketone
18 was screened for biocatalytic reductive amination. Several
mutant libraries of wild-type SpRedAm from Streptomyces
purpureus were designed and tested, resulting in a suitable
enzyme that provided the desired cis-amino ester 19 in 74%
yield with a >99:1 diastereomeric ratio after isolation as the
succinate salt. The discovery route (Scheme 2) employed
tosylated pyrrolopyrimidine 11 to facilitate the SNAr reaction.
While this worked well with amine 19, the tosyl protecting
group was incompatible with the hydroxylamine required to
generate the Lossen reaction precursor. During development, it
was found that unprotected pyrrolopyrimidine 2 was
competent for the SNAr reaction with an extended reaction
time. The fusion of 2 and 19 was optimized to provide 20 in
81% isolated yield. Treatment of ester 20 with hydroxylamine
hydrochloride in NaOMe and MeOH afforded hydroxamic
acid 16 in 94% yield.
The Lossen rearrangement was then evaluated. Several
reagents were tested, and 1,1′-carbonyldiimidazole (CDI)
emerged as effective at promoting the rearrangement while
minimizing byproduct generation. Acidic hydrolysis was
required to avoid urea formation, and a screen revealed that
phosphoric acid was much more efficient than other mineral
acids. After addition of phosphoric acid and pH adjustment,
amine phosphate salt 17 was isolated in 81% yield. An X-ray
crystal structure of intermediate 17 was obtained that
confirmed the critical cis configuration.22 Analytical tracking
of the intermediates, avoidance of haloarenes/phosphoryl azide
reagents, and intermediate physical properties rendered the
Lossen rearrangement ideal for large-scale manufacturing.
The diaminocyclobutane structure requires sulfonylation to
complete the synthesis of 1. As previously described in the
enabling route, the API can be accessed through direct
sulfonylation of amine 13 using 14 in organic solvents
(Scheme 2). Sulfonylation of amine 17 requires a different
approach because of its poor solubility in organic solvents, high
solubility in acidic or basic aqueous solutions, reactive
heterocyclic core, and reaction hetereogeneity due to
complications with residual phosphate salts. The sulfonylation
may be conducted in basic aqueous media using 14, but this
also results in sulfonylation of the pyrrolopyridimine nitrogen
in addition to competitive degradation of the sulfonyl chloride.
This was more successful at low temperature, but the
scalability was limited because of the risk of freezing of
aqueous media at very low temperatures.
Therefore, a series of alternative sulfonylation reagents were
generated and evaluated in organic and aqueous solvent
mixtures (Figure 2). These provided less reactive, more stable
Figure 2. Sulfonyl transfer reagents.
alternatives to 14. Each reagent was evaluated for safety,
stability, relative reactivity, and impurity formation. A
combination of safety concerns and undesirable reactivity
eliminated 22 and 23. Imidazolium 24 exhibited excellent
reaction kinetics, but an observed methylation impurity was
undesirable. Comins’ inspired reagent23 25 was an attractive
option in terms of its physical handling, safety profile, and
reaction kinetics, but the cost of purchasing large quantities of
the reagent would necessitate developing a method to recover
and recycle the reagent. Propane-1-sulfonyl fluoride (26) was
also evaluated, but the cost of the custom reagent, lack of a
chromophore, and concerns about reactor etching with free
fluoride were deterrents.
1,2,4-Triazole derivative 21 emerged as the lead sulfonylat-
ing agent on the basis of its excellent stability in aqueous
systems, fast reaction kinetics, and an acceptable safety profile.
This was generated by suspension of 1,2,4-triazole in THF.
C
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1
Following aqueous workup, 21 could be generated as a
solution in THF or concentrated to an oil. After salt break of
17 in THF with NaOH, 21 could be added as a solution in
THF. Addition of water resulted in crystallization of the
product 1 in 84% isolated yield.
oven at 50 °C to afford amide 15 (686 mg, 57% yield). H
NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.97 (d, J = 8.4
Hz, 2H), 7.63 (d, J = 4.1 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H),
7.31 (s, 1H), 6.96 (d, J = 4.1 Hz, 1H), 6.82 (s, 1H), 5.07 (p, J
= 8.6 Hz, 1H), 3.22 (s, 3H), 2.70 (p, J = 8.6 Hz, 1H), 2.40−
2.26 (m, 7H); 13C NMR (101 MHz, DMSO-d6) δ 175.6,
157.1, 152.8, 151.7, 146.2, 134.9, 130.4, 128.2, 122.0, 106.9,
104.8, 47.3, 32.2, 31.7, 31.0, 21.6; IR (cast film, cm−1) 1663,
1567, 1494, 1417, 1371, 1341, 1283, 1260, 1189, 1157, 1089,
1062, 813, 797, 712, 669, 630, 604, 595; mp 145−148 °C;
HRMS (TOF) m/z calcd for C19H21N5O3S+ ([M + H]+)
400.1443, found 400.1433.
CONCLUSION
■
A commercial route to the JAK1 inhibitor abrocitinib was
developed, including a biocatalytic reductive amination to
afford the cis-cyclobutane ring, an SNAr reaction to incorporate
the unprotected pyrrolopyrimidine core, a Lossen rearrange-
ment, and sulfonylation using a novel reagent for sulfonyl
transfer. The execution of this new route for clinical and
commercial supply is currently underway.24
(1S,3S)-N1-Methyl-N1-(7-tosyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)cyclobutane-1,3-diamine Dihydrobro-
mide (13). Amide 15 (500 mg, 1.0 equiv) was charged to a
vial and dissolved in DMF (5 mL), acetonitrile (5 mL), and
water (5 mL). Bis(acetoxy)iodobenzene (492 mg, 1.2 equiv)
was then charged, and the reaction mixture was stirred. Once
the reaction was deemed to be complete, the solution was
transferred dropwise into a KOH (350 μL, 11.5 M)/water (5
mL) quench solution. The amine was then extracted with
DCM (15 mL), washed with brine (2 × 10 mL), and dried
with MgSO4. The solution was then concentrated, and water
was removed via azeotroping with 2-MeTHF (2 × 5 mL). The
resulting oil was dissolved in DCM (2 mL), and a 33% solution
of HBr in acetic acid was added (0.65 mL, 3.0 equiv). The
orange solution was added dropwise into ethyl acetate (10
mL), resulting in immediate precipitation. The solids were
filtered and isolated (598 mg), and their spectroscopic data
matched those of previously isolated samples. The material
could be reslurried in DCM to further improve the purity (384
mg, 58% yield). The spectroscopic data for this material
matched that previously reported.
EXPERIMENTAL PROCEDURES
■
Characterization data for compounds 10, 11, 12, 13, and 1
have been reported previously.10
Synthesis of Abrocitinib (1) from 13. Dihydrobromide
salt 13 (10.0 g, 18.8 mmol, 1.0 equiv) and 2-MeTHF (100
mL) were charged to a 250 mL reactor at 25 °C. Triethylamine
(15.7 mL, 113 mmol, 6 equiv) was added in a single portion,
and the mixture was stirred for 1 h and then cooled to −10 °C.
Next, propane-1-sulfonyl chloride (14) (3.59 mL, 31.9 mmol,
1.7 equiv) was added dropwise while the temperature was
maintained below 0 °C. The reaction mixture was stirred at
−10 °C until the reaction was complete and then warmed to 0
°C and quenched by the addition of water (100 mL). The
solution was warmed to 25 °C, stirred for 10 min, and then
transferred to a separatory funnel. The bottom layer was
discarded, and the top layer transferred back to the reaction
flask. Darco G60 (1 g) was added, and the mixture was stirred
at 25 °C for 1 h and then filtered over a pad of Celite. The
Celite cake was rinsed with 2-MeTHF (40 mL), and the filtrate
was placed back into the reaction flask. A solution of 10%
aqueous NaOH (100 mL) was then charged, and the mixture
was heated to 70 °C for 4 h, cooled to room temperature, and
transferred to a separatory funnel. The layers were separated,
and the organic layer was extracted with 10% aqueous NaOH
(50 mL). The extract was combined with the aqueous layer
and transferred back to the reaction vessel. The pH was
adjusted to 6−7 with 6 N HCl, and the slurry was granulated at
ambient temperature for >12 h. The slurry was then filtered,
and the solid was rinsed with water (30 mL) and dried in a
vacuum oven at 50 °C to afford 1 (5.39 g, 89% yield) as an off-
white solid.
(1S,3S)-3-[Methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)amino]cyclobutane-1-carboxamide (15). To a 20 mL
Schlenk tube, cis-3-(methylamino)cyclobutane-1-carboxamide
hydrochloride salt (500 mg, 1.0 equiv), isopropyl alcohol (4
mL), 4-chloropyrrolopyrimidine 11 (1.03 g, 1.1 equiv), and
DBU (0.97 g, 2.1 equiv) were charged. The mixture was
heated to 85 °C and stirred until the reaction was complete by
UPLC. The mixture was cooled to 40 °C, and water (20 mL)
was added, resulting in a clear solution. Cooling was continued
to 20 °C to form a slurry. The solids were filtered and rinsed
with water (30 mL). The crude solids (1.18 g) were purified by
reversed-phase chromatography (gradient of 2:3 MeOH/H2O
to 100% MeOH, 20 column volumes (CV)). The desired
fractions were combined, and the methanol was removed in
vacuo, resulting in the precipitation of a white solid. The solid
was filtered, rinsed with water (10 mL), and dried in a vacuum
Isopropyl 3-Oxocyclobutane-1-carboxylate (18).
Commercially available isopropyl 3-oxocyclobutane-1-carbox-
ylate (3) (84.6 g, 1.0 equiv) was dissolved in 2-propanol (500
mL) and p-toluenesulfonic acid monohydrate was added (5.56
g, 4 mol %, 0.04 equiv). The solution was heated to 80 °C and
stirred for 19 h, at which point the reaction was deemed to be
1
complete by H NMR analysis. The reaction mixture was
cooled to 40 °C, transferred to a 1 L separatory funnel, diluted
with methyl tert-butyl ether (MTBE) (200 mL), and washed
with saturated sodium bicarbonate (3 × 100 mL), and the
layers were separated. The aqueous layer was discarded, and
the organic layer was washed with brine (2 × 50 mL). The
MTBE layer was dried with sodium sulfate and then
concentrated at 40 °C at 25 Torr to afford 18 as a pale-
yellow oil (101.6 g, 90.5% yield). 1H NMR (400 MHz,
DMSO-d6) δ 4.95 (hept, J = 6.3 Hz, 1H), 3.38−3.18 (m, 5H),
1.22 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz, DMSO-d6)
203.9, 173.5, 68.7, 51.5, 27.6, 21.7; IR (cast film, cm−1) 3126,
3077, 2982, 1790, 1721, 1525, 1401, 1248, 1223, 1170, 1114,
1076, 1088, 1028, 1014, 768, 746, 640; HRMS (ESI) m/z
calcd for C8H13O3 ([M + H]+) 157.08647, found 157.0857.
+
Propan-2-yl (1S,3S)-3-(Methylamino)cyclobutane-1-
carboxylate Butanedioic Acid (1:1) (19). To a 100 mL
EasyMax reactor was charged potassium phosphate buffer (40
mL, pH 7.2, 100 mM) at 25 °C, followed by methylamine
hydrochloride (3.25 g, 1.5 equiv) and glucose monohydrate
(7.5 g, 1.3 equiv). The reaction mixture was stirred until
homogeneous, and the pH was adjusted to 7 using 20 wt %
aqueous sodium hydroxide. Ketone 18 (5.0 g, 1.0 equiv)
followed by DMSO (2.5 mL) was charged to the reactor.
D
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NADP+ (12.5 mg, 0.0005 equiv), GDH (12.5 mg, 0.25 wt %
relative to 18), and the custom enzyme SpRedAm (125 mg)
were added. The reaction mixture was held at 25 °C for 72 h,
using a pH dosing unit to maintain a constant pH of 7 via
titration with 20% aqueous sodium hydroxide solution. When
the reaction was complete, the reactor was cooled to 3 °C, and
pH was adjusted to 3.3 with aqueous hydrochloric acid (12.2
M). After the mixture was stirred for 30 min, carbon (1.0 g, 2.6
equiv) was charged and the suspension was stirred for an
additional 30 min. The carbon was filtered through a layer of
Celite and rinsed with water (5 mL). MTBE (100 mL) was
charged, and the mixture was cooled to 5 °C, after which
aqueous NaOH (20 wt %) was dosed until the pH was 12.3.
The phases were split, and the organic layer was collected and
concentrated under vacuum (500 mbar) to a final volume of
25 mL. Fresh MTBE (50 mL) was added.
In a separate vessel, MTBE (50 mL) and succinic acid (3.40
g, 0.90 equiv) were charged to a reactor at 20 °C. Seed crystals
of 19 (0.05 g, 0.005 equiv) were added, followed by the
addition of the MTBE solution of the amine via addition
funnel. The resulting slurry was granulated for 1 h at 20 °C.
The solids were filtered, rinsed with MTBE (25 mL), and dried
in a vacuum oven at 40 °C to afford the desired amine
succinate salt 19 (6.86 g, 74% yield) as a white solid. 1H NMR
(400 MHz, DMSO-d6) δ 10.66 (br s, 2H), 4.88 (hept, J = 6.2
Hz, 1H), 3.30 (tt, J = 8.8, 7.3 Hz, 1H), 2.82 (tt, J = 9.8, 8.2 Hz,
1H), 2.43−2.34 (m, 2H), 2.31 (d, J = 2.5 Hz, 7H), 2.13−2.00
(m, 2H), 1.18 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz,
DMSO-d6) δ 174.9, 173.1, 67.3, 48.8, 31.1, 30.6, 30.4, 21.5; IR
(cast film, cm−1) 2987, 2745, 2502, 1720, 1637, 1519, 1377,
1351, 1254, 1191, 1098, 1070, 1017, 875, 801, 755, 669, 585;
mp 88−89 °C; HRMS (TOF) m/z calcd for C9H17NO2+ ([M
+ H]+) 172.1338, found 172.1329.
resulting in a slight endotherm. Ester 20 (50 g, 1.0 equiv)
was then added, resulting in a white slurry. The reaction
mixture was warmed to 40 °C and stirred overnight, and the
reaction was deemed to be complete by UPLC-MS. To the
now-thick slurry was charged hydrochloric acid (1 M, 208 mL)
until pH 7.0 was achieved. The slurry was then filtered and
rinsed with methanol (100 mL). The material was dried in a
vacuum oven overnight to afford 16 (42.7 g, 94% yield) as a
white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H),
10.47 (s, 1H), 8.80 (s, 1H), 8.09 (s, 1H), 7.14 (d, J = 3.6 Hz,
1H), 6.60 (d, J = 3.5 Hz, 1H), 5.21 (p, J = 8.8 Hz, 1H), 3.33 (s,
3H), 2.61 (p, J = 8.4 Hz, 1H), 2.43 (dt, J = 11.5, 9.1 Hz, 2H),
2.32 (qd, J = 8.0, 2.6 Hz, 2H); 13C NMR (100 MHz, DMSO-
d6) 170.2, 156.7, 151.7, 150.5, 120.9, 102.4, 101.3, 46.7, 31.4,
30.5, 28.7; IR (cast film, cm−1) 3227, 3112, 3044, 2938, 2541,
1580, 1515, 1491, 1453, 1417, 1372, 1340, 1323, 1266, 1111,
1023, 882, 739, 673, 604; mp, decomposes above 158 °C;
+
HRMS (TOF) m/z calcd for C12H16N5O2 ([M + H]+)
262.1304, found 262.1295.
(1S,3S)-N1-Methyl-N1-(7H-pyrrolo[2,3-d]pyrimidin-4-
yl)cyclobutane-1,3-diamine Phosphoric Acid (1:1) (17).
Hydroxamic acid 16 (19.4 g, 1.0 equiv) was charged to a
reactor, followed by 2-MeTHF (388 mL), resulting in a white
slurry. The slurry was warmed to 30 °C, and 1,1′-carbon-
yldiimidazole (16.1 g, 1.3 equiv) was added. The reaction
mixture was stirred overnight, at which point the reaction was
deemed to be complete by UPLC-MS. A solution of
phosphoric acid (14.7 M in water, 25.5 mL, 5.0 equiv) was
diluted with water (78 mL) and added slowly to the slurry.
The slurry dissolved, and the reaction mixture was heated to 60
°C and held for several hours. When the reaction was deemed
to be complete, sodium hydroxide (20 wt % in water, 16.4 mL,
1.45 equiv) was added to obtain 17. The reaction mixture was
warmed to 80 °C and then cooled to 25 °C. 2-Propanol (58
mL) was added slowly, and the solid was filtered. The cake was
washed with 2-propanol/water (1:1 v/v, 40 mL) and dried in a
vacuum oven to afford 17 (19.1 g, 81% yield). Crystals suitable
for X-ray analysis were grown by heating a sample (1.34 g) in
IPA (27 mL) and adding water with heat cycling (20−75 °C).
1H NMR (400 MHz, D2O) δ 7.78 (s, 1H), 6.96 (d, J = 3.6 Hz,
1H), 6.28 (d, J = 3.6 Hz, 1H), 4.52 (s, 1H), 3.60 (s, 1H), 3.00
(s, 3H), 2.67 (dd, J = 9.8, 2.7 Hz, 2H), 2.39 (dd, J = 9.4, 3.1
Hz, 2H); 13C NMR (101 MHz, D2O) δ 158.8, 151.6, 151.6,
124.4, 105.3, 104.9, 48.8, 42.0, 35.9, 34.6; 31P NMR (162
MHz, D2O) δ 0.31; IR (cast film, cm−1) 1582, 1504, 1423,
1387, 1345, 1327, 1244, 1192, 1078, 1032, 948, 913, 879, 762,
728, 696, 635, 620, 607, 564, 538; mp >250 °C; HRMS
(TOF) m/z calcd for C11H16N5+ ([M + H]+) 218.1406, found
218.1396.
1-(Propylsulfonyl)-1H-1,2,4-triazole (21). 1,2,4-Triazole
(11.98 g, 2.5 equiv) and THF (40 mL) were charged to an EZ
Max reactor equipped with overhead stirring. The suspension
was stirred for 10 min, and then propane-1-sulfonyl chloride
(7.89 mL, 1.0 equiv) was added at 20 °C. The resulting slurry
was stirred at 20 °C until the starting material was consumed
as judged by 1H NMR analysis. Once the reaction was
complete, the reaction mixture was filtered, and the filtrate was
transferred to a separatory funnel, where it was diluted with
water (20 mL) and extracted with dichloromethane (50 mL).
The layers were separated, and the DCM layer was washed
with water (2 × 20 mL) and brine (1 × 20 mL). The organic
layer was dried with MgSO4, filtered, and concentrated in
vacuo to afford sulfonyl triazole 21 (10.66 g, 89% yield) as a
Propan-2-yl (1S,3S)-3-[Methyl(7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)amino]cyclobutane-1-carboxylate (20).
Succinate salt 19 (75.4 g, 1.0 equiv) and 4-chloropyrrolopyr-
imidine (2) (40.0 g, 1.0 equiv) were combined in a reactor. 2-
Propanol (200 mL) was charged, resulting in a slurry.
Diisopropylethylamine (114 mL, 2.5 equiv) was charged,
resulting in a thin slurry. The reaction mixture was heated to
80 °C, forming a solution, which was held at 80 °C until the
reaction was deemed to be complete by UPLC-MS
(approximately 48 h). The reaction mixture was cooled to
20 °C and became a slurry. The solids were filtered and
washed with two portions of 2-propanol (80 mL each) to
afford the desired product (61 g, 81% yield) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.12 (s, 1H),
7.16 (dd, J = 3.6, 2.3 Hz, 1H), 6.62 (dd, J = 3.6, 1.7 Hz, 1H),
5.25 (tt, J = 9.4, 7.9 Hz, 1H), 4.92 (hept, J = 6.3 Hz, 1H), 3.26
(s, 3H), 2.88 (tt, J = 9.2, 8.0 Hz, 1H), 2.49−2.36 (m, 4H), 1.21
(d, J = 6.3 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) 173.6,
156.7, 151.8, 150.5, 121.0, 102.5, 101.3, 67.3, 46.5, 31.3, 30.9,
30.5, 21.6; IR (cast film, cm−1) 3090, 2978, 2839, 1719, 1566,
1509, 1489, 1413, 1346, 1336, 1230, 1104, 1124, 1040, 1026,
948, 876, 832, 815, 733, 715, 655, 625; mp 177−178 °C;
+
HRMS (TOF) m/z calcd for C15H21N4O2 ([M + H]+)
289.1665, found 289.1657.
(1S,3S)-N-Hydroxy-3-[methyl(7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)amino]cyclobutane-1-carboxamide (16).
To a reactor were charged methanol (500 mL) and sodium
methoxide in methanol (93.7 mL, 25 wt %, 2.4 equiv) under
nitrogen. Hydroxylamine hydrochloride (15.1 g, 1.25 equiv)
was charged to the room-temperature reaction mixture,
E
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viscous, clear colorless oil. 1H NMR (400 MHz, chloroform-d)
δ 8.67 (s, 1H), 8.13 (s, 1H), 3.55−3.46 (m, 2H), 1.76 (h, J =
7.5 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz,
chloroform-d) δ 154.4, 145.3, 55.9, 16.9, 12.5; IR (cast film,
cm−1) 3129, 2975, 1502, 1459, 1371, 1325, 1269, 1168, 1137,
1099, 981, 946, 875, 775, 737, 713, 667, 629, 606, 541; HRMS
(TOF) m/z calcd for C5H10N3O2S+ ([M + H]+) 176.0494,
found 176.0488.
A sample of this material was analyzed via differential
scanning calorimetry (DSC) in a sealed high-pressure gold-
plated crucible and showed 3 exothermic peaks, the first with
an onset of 90 °C and an energy of 32 J/g, the second with an
onset of 133 °C and an energy of 495 J/g, and the third with
an onset of 198 °C and an energy of 29 J/g. End users of 21 are
strongly advised to conduct internal safety testing and analysis,
including DSC and explosivity testing.
Synthesis of 1 via 21. Water (18 mL) and phosphate salt
17 (3.0 g, 1.0 equiv) were charged to a reactor, followed by
sodium hydroxide in water (19 M, 1.5 mL, 3.0 equiv). The
reaction exhibited a slight exotherm and was cooled to 25 °C.
Propanesulfonyltriazole 21 (4.3 g, 2.5 equiv) was dissolved in
THF (12 mL) and added to the hydroxide reaction mixture.
Once the reaction was deemed to be complete, water (18 mL)
was added, and the material was filtered and dried to afford the
product 1 (2.57 g, 84% yield) as a solid.
Abrocitinib (1) via In Situ-Generated 21. The lithium
salt of 1,2,4-triazole was prepared using the procedure
disclosed in the literature.23 This lithium salt (1.0 g, 2.1
equiv) and THF (8 mL) were charged to a reactor at 20 °C,
followed by 14 (1.47 mL, 2.0 equiv). The slurry was stirred at
20 °C until 14 was consumed, as judged by 1H NMR analysis.
In a separate flask, phosphate salt 17 (2.0 g, 1.0 equiv) was
dissolved in water (12 mL) at 20 °C, and then 50 wt %
aqueous sodium hydroxide (1.0 mL, 3.0 equiv) was added
while the temperature was kept below 30 °C. The aqueous
solution was cooled to 10 °C, and then the THF solution of
the sulfonyltriazole reagent was added while the temperature
was maintained below 20 °C. The resulting suspension was
stirred until <5% of the amine remained according to UPLC-
MS. Then 50 wt % aqueous sodium hydroxide (0.67 mL, 2.0
equiv) was added, and the reaction mixture was heated to 50
°C. Once the sulfonyltriazole reagent was consumed as
determined by UPLC-MS, the reaction mixture was cooled
to 20 °C, and hydrochloric acid (6 N) was added to achieve
pH 5−6. The resulting slurry was cooled to 10 °C, held for 30
min, and filtered. The cake was rinsed with H2O/THF (75:25
v/v, 10 mL), and the solid was dried at 50 °C in a vacuum
oven to afford the desired product as an off-white solid (2.33 g,
114% yield due to inorganic salts). To remove the salts, 1.04 g
of the crude solid was suspended in H2O (8 mL)/THF (2 mL)
at 40 °C. After 15 min of stirring, the slurry was filtered, rinsed
with H2O/THF (4:1 v/v, 2 mL), and dried to afford the
product 1 (825 mg, 79% recovery) as a solid.
as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H),
7.29 (s, 1H), 7.18 (s, 1H), 3.30−3.26 (m, 2H), 1.76 (sextet, J
= 7.7 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 137.1, 131.5, 117.8, 57.8, 17.3, 12.6; IR (cast film,
cm−1) 3126, 2974, 1520, 1458, 1368, 1250, 1166, 1149, 992,
865, 829, 777, 738, 715, 649, 626, 613, 596, 556, 545; HRMS
(TOF) m/z calcd for C6H11N2O2S+ ([M + H]+) 175.0541,
found 175.0534.
A sample of this material was analyzed via DSC in a sealed
high-pressure gold-plated crucible and showed three exother-
mic peaks, the first with an onset of 81 °C and an energy of 18
J/g, the second with an onset of 118 °C and an energy of 662
J/g, and the third with an onset of 317 °C and an energy of
118 J/g. End users of 22 are strongly advised to conduct internal
safety testing and analysis, including DSC and explosivity testing.
1-(Propylsulfonyl)-1H-benzo[d]imidazole (23). Benzi-
midazole (500 mg, 4.23 mmol, 1.0 equiv) was dissolved in
DCM (5 mL) and Et3N (1.47 mL, 2.5 equiv). To this solution
was added propane-1-sulfonyl chloride (0.74 mL, 1.5 equiv),
and the reaction mixture was stirred at room temperature.
When the reaction was complete, water (5 mL) was added.
The layers were separated, and the aqueous layer was extracted
with DCM (5 mL). The organic layers were combined and
concentrated in vacuo, and the crude solid was purified by
column chromatography (1 CV heptanes, 9 CV ramp from
100% heptanes to 100% EtOAc, 2 CV EtOAc) to afford the
desired product (800 mg, 84% yield) as an oil. 1H NMR (400
MHz, CDCl3) δ 8.30 (s, 1H), 7.90−7.80 (m, 2H), 7.50−7.37
(m, 2H), 3.41−3.31 (m, 2H), 1.83−1.66 (m, 2H), 1.01 (t, J =
7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 143.7, 141.6,
131.2, 126.0, 125.3, 121.3, 112.4, 56.7, 17.2, 12.7; IR (cast film,
cm−1) 3973, 1697, 1608, 1500, 1475, 1369, 1253, 1193, 1157,
1135, 1086, 1066, 1033, 1011, 883, 765, 743, 715, 667, 616,
598, 581, 568, 538; HRMS (TOF) m/z calcd for
C10H13N2O2S+ ([M + H]+) 225.0698, found 225.0690.
A sample of this material was analyzed via DSC in a sealed
high-pressure gold-plated crucible and showed two exothermic
peaks, the first with an onset of 126 °C and an energy of 543 J/
g and the second with an onset of 263 °C and an energy of 87
J/g. End users of 23 are strongly advised to conduct internal safety
testing and analysis, including DSC and explosivity testing.
3-Methyl-1-(propylsulfonyl)-1H-imidazol-3-ium Tri-
fluoromethanesulfonate (24). Sulfonyl imidazole 22 (2.9
g, 1.0 equiv) was dissolved in Et2O (44 mL) and cooled to 5
°C, and then methyl trifluoromethanesulfonate (1.9 mL, 1.0
equiv) was added dropwise over 10 min. The reaction mixture
was stirred at 5 °C for 30 min, during which time a white
precipitate formed. The reaction mixture was warmed to 10 °C
and then filtered. The solids were rinsed with Et2O (20 mL)
and dried in a vacuum oven at 50 °C to afford 24 (4.8 g, 85%
yield) as a white solid. 1H NMR (400 MHz, acetone-d6) δ 9.57
(s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 4.17 (s, 3H), 4.12−3.98
(m, 2H), 1.91 (h, J = 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, acetone-d6) δ 139.6, 126.6, 121.9 (q, J =
321.1 Hz), 121.5, 57.6, 37.7, 17.6, 12.3; 19F NMR (376 MHz,
acetone-d6) δ −78.98; IR (cast film, cm−1) 3126, 3078, 1586,
1525, 1459, 1401, 1339, 1250, 1224, 1168, 1114, 1088, 1076,
1028, 986, 926, 888, 767, 746, 709, 672, 641, 631, 621, 575,
556, 548, 535, 529; mp 67−68 °C; HRMS (TOF) m/z calcd
for C7H13N2O2S+ (M+) 189.0698, found 189.0691.
1-(Propylsulfonyl)-1H-imidazole (22). A reactor was
charged with dichloromethane (203 mL) followed by propane-
1-sulfonyl chloride (20 mL, 1.0 equiv) and cooled to 0 °C.
Imidazole (2.42 g, 2.0 equiv) was added portionwise over
approximately 12 min, and the reaction mixture was held at 0
°C for 30 min. The reaction was deemed to be complete by
UPLC-MS, and the reaction mixture was warmed to 20 °C and
charged with water. The aqueous layer was discarded, and the
dichloromethane solution was dried with brine and MgSO4.
The material was concentrated to give 22 (2.48 g, 80% yield)
A sample of this material was analyzed via DSC in a sealed
high-pressure gold-plated crucible and showed two exothermic
peaks, the first with an onset of 98 °C and an energy of 474 J/g
F
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Communication
Authors
and the second with an onset of 330 °C and an energy of 477
J/g. End users of 24 are strongly advised to conduct internal safety
testing and analysis, including DSC and explosivity testing.
Christina G. Connor − Chemical Research & Development,
Pfizer Worldwide Research & Development, Groton,
Connecticut 06340, United States
Jacob C. DeForest − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Phil Dietrich − Analytical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Kevin M. Doyle − Analytical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Shane Eisenbeis − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Elizabeth Greenberg − Analytical Research & Development,
Pfizer Worldwide Research & Development, Groton,
Connecticut 06340, United States
Sarah H. Griffin − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Brian P. Jones − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Kris N. Jones − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Michael Karmilowicz − Chemical Research & Development,
Pfizer Worldwide Research & Development, Groton,
Connecticut 06340, United States
Rajesh Kumar − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Emma L. McInturff − Chemical Research & Development,
Pfizer Worldwide Research & Development, Groton,
Connecticut 06340, United States; orcid.org/0000-0003-
0426-3089
J. Christopher McWilliams − Chemical Research &
Development, Pfizer Worldwide Research & Development,
Groton, Connecticut 06340, United States; orcid.org/0000-
0002-4764-735X
Ruchi Mehta − Analytical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Bao D. Nguyen − Analytical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Anil M. Rane − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
N-(5-Chloropyridin-2-yl)-N-(propylsulfonyl)propane-
1-sulfonamide (25). DCM (50 mL) and Et3N (43.4 mL, 4.0
equiv) were added to a 250 mL vessel equipped with overhead
stirring, followed by 2-amino-5-chloropyridine (10 g, 1.0
equiv). The mixture was cooled to −20 °C, and then DMAP
(490 mg, 0.05 equiv) was added. Next, propane-1-sulfonyl
chloride (26.3 mL, 3.0 equiv) was added via syringe pump at 5
mL/h while the internal temperature was kept below −10 °C.
When the addition was complete, the reaction mixture was
stirred for 30 min and then warmed to −10 °C, and water was
added (50 mL). The reaction mixture was warmed to room
temperature, and the layers were separated. The aqueous layer
was extracted with DCM (2 × 50 mL), and the organic layers
were combined, washed with water (2 × 50 mL), dried with
sodium sulfate, filtered over Celite, and concentrated in vacuo
to afford a red oil. Methylcyclohexane (100 mL) was added to
the oil, and the mixture was warmed with vigorous stirring
until all of the solids had dissolved. The mixture was then
cooled slowly to room temperature, and heptane (100 mL)
was added, which resulted in precipitation. The slurry was
stirred for 30 min, filtered, and rinsed with heptane (100 mL).
The solids were dried in a vacuum oven at 50 °C overnight to
afford the desired product 25 (24.9 g, 93.9% yield) as a tan
1
solid. H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.7 Hz,
1H), 8.18 (dd, J = 8.5, 2.7 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H),
3.78 (dd, J = 8.5, 6.7 Hz, 4H), 1.87 (h, J = 7.8 Hz, 4H), 1.03 (t,
J = 7.4 Hz, 6H); 13C NMR (101 MHz, DMSO-d6) δ 148.1,
146.5, 139.5, 132.7, 127.2, 57.4, 16.4, 12.5; IR (cast film,
cm−1) 2965, 1547, 1457, 1211, 1370, 1346, 1291, 1257, 1206,
1150, 1125, 1111, 1088, 1017, 982, 954, 926, 913, 834, 779,
750, 737, 708, 641, 614, 579; mp 69−70 °C; HRMS (TOF)
m/z calcd for C11H18ClN2O4S2 ([M + H]+) 341.0397, found
+
341.0391.
A sample of this material was analyzed via DSC in a sealed
high-pressure gold-plated crucible and showed an exothermic
peak with an onset of 204 °C and an energy of 669 J/g. End
users of 25 are strongly advised to conduct internal safety testing
and analysis, including DSC and explosivity testing.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00366.
General procedures, preparation of 6 and 9, DSC data
for 14 and 27, NMR spectra, NMR spectra, crystallo-
graphic data for (PDF)
Crystallographic data for 17 (CIF)
Brian Samas − Drug Product Design, Pfizer Worldwide Research
& Development, Groton, Connecticut 06340, United States
Barbara J. Sitter − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
AUTHOR INFORMATION
■
Corresponding Authors
Chad A. Lewis − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States; orcid.org/0000-0002-2000-6456;
Email: chad.lewis@pfizer.com
Nga M. Do − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States; Email: nga.m.do@pfizer.com
Howard W. Ward − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
∥Mark E. Webster − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
G
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Communication
(12) Hu, E.; Andrews, K.; Chmait, S.; Zhao, X.; Davis, C.; Miller, S.;
Hill Della Puppa, G.; Dovlatyan, M.; Chen, H.; Lester-Zeiner, D.;
Able, J.; Biorn, C.; Ma, J.; Shi, J.; Treanor, J.; Allen, J. R. Discovery of
Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of
Phosphodiesterase 10A (PDE10A). ACS Med. Chem. Lett. 2014, 5
(6), 700−705.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00366
Author Contributions
All of the authors approved the final version of the manuscript.
́
(13) Aube, J.; Fehl, C.; Liu, R.; McLeod, M. C.; Motiwala, H. F. 6.15
Notes
Hofmann, Curtius, Schmidt, Lossen, and Related Reactions. In
Comprehensive Organic Synthesis II, 2nd ed.; Knochel, P., Ed.; Elsevier:
Amsterdam, 2014; pp 598−635.
(14) Sun, X.; Rai, R.; Deschamps, J. R.; MacKerell, A. D., Jr.; Faden,
A. I.; Xue, F. Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step
Curtius rearrangement: mechanism and scope. Tetrahedron Lett.
2014, 55 (4), 842−844.
(15) Zhang, L.-h.; Chung, J. C.; Costello, T. D.; Valvis, I.; Ma, P.;
Kauffman, S.; Ward, R. The Enantiospecific Synthesis of Isoxazoline
DMP754, a RGD Mimic Platelet GPIIb/IIIa Antagonist. J. Org. Chem.
1997, 62 (8), 2466−2470.
(16) Abrecht, S.; Adam, J.-M.; Bromberger, U.; Diodone, R.; Fettes,
A.; Fischer, R.; Goeckel, V.; Hildbrand, S.; Moine, G.; Weber, M. An
Efficient Process for the Manufacture of Carmegliptin. Org. Process
Res. Dev. 2011, 15 (3), 503−514.
(17) Daver, S.; Rodeville, N.; Pineau, F.; Arlabosse, J.-M.; Moureou,
C.; Muller, F.; Pierre, R.; Bouquet, K.; Dumais, L.; Boiteau, J.-G.;
Cardinaud, I. Process Development and Crystallization in Oiling-Out
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The authors declare no competing financial interest.
∥M.E.W.: deceased January 6, 2019.
CCDC 2005131 contains the supplementary crystallographic
data for this paper. These data can be obtained via www.ccdc.
cam.ac.uk/data_request/cif or data_request@ccdc.cam.ac.uk.
ACKNOWLEDGMENTS
■
Natalie Beland (Pfizer) is thanked for the ReactIR studies. Ivan
Samardjiev (Pfizer) is acknowledged for the X-ray crystal
structure data collection. John Weaver (Pfizer) is thanked for
obtaining DSC data for intermediates.
DEDICATION
■
This paper is dedicated to the memory of Mark Webster.
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