Preparation of Methyltriazolo[1,4]benzodiazepine via Oxidative Activation of a Thiolactam for the Synthesis of BET Inhibitor Molibresib

Article abstract of DOI:10.1021/acs.joc.1c00563

A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.

Full text of DOI:10.1021/acs.joc.1c00563

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Article
Preparation of Methyltriazolo[1,4]benzodiazepine via Oxidative
Activation of a Thiolactam for the Synthesis of BET Inhibitor
Molibresib
Greg A. Erickson, Mark A. Hatcher, Michel Journet, John A. Kowalski, Tom C. Lovelace,
Christopher J. Pink, and Shiping Xie*
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ABSTRACT: A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine
in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of
acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was
scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was
prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The
concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the
methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the
known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.
preparative HPLC to give GSK525762 (1) and its (R)-
enantiomer 13.
INTRODUCTION
■
The interaction between bromo and extra-terminal (BET)
bromodomain proteins and their acetylated histone substrates
has recently attracted extensive attention in the field of
epigenetics.1 GSK525762 (1, generic name molibresib, Figure
1) is a potent inhibitor of the BET family of proteins, and it
prevents the binding required for macromolecular complex
assembly and the subsequent transcriptional response.2a The
initial clinical development of 1 focused on the treatment of
advanced solid tumors.2b A notable structural feature of 1 is
the 1-methyltriazolo[1,4]benzodiazepine substructure. This
scaffold is also present in several other BET inhibitors
including JQ1 (2),3 OTX-015 (3),4 and compound ET (4),5
as shown in Figure 1. Compounds 2 and 3 were also clinical
stage drug candidates for oncology.
The original synthesis of 1 by medicinal chemistry is shown
in Scheme 1.2a The racemic synthesis started with 2-
aminobenzophenone 5, which reacted with racemic acyl
chloride 6 to provide lactam 7 through three distinctive
steps: amide formation, Fmoc cleavage, and cyclocondensa-
tion. Thionation with Lawesson’s reagent gave thiolactam 8. A
three-step process was used to convert 8 to a methyltriazole:
formation of hydrazone 9, acetylation for 10, and ring closure
with acetic acid to give 11. Ester hydrolysis followed by amide
formation gave racemic target 12, which was resolved by
Subsequently, the racemic synthesis shown in Scheme 1 was
upgraded by a team of chemists in Early Development and
Supply to a chiral version to deliver multikilograms of 1 by
replacing the racemic 6 with (S)-6 derived from L-aspartic acid.
However, the three-step sequence from the thiolactam to the
methyltriazole was cumbersome regarding workups and
purifications needed. During the scaleup of the chiral synthesis
involving intermediates 14 and 15, we discovered that a
dihydropyridazinone side product (17) inevitably formed from
hydrazone 16, as shown in Scheme 2. It was not an issue in the
racemic synthesis as chromatographic purification was used on
a small scale to remove the impurity. Although the impurity
was significantly less soluble than the product, it took several
crystallizations to remove it to below a specification level on a
large scale.
Special Issue: Excellence in Industrial Organic Syn-
thesis 2021
Received: March 9, 2021
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© XXXX American Chemical Society
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Figure 1. Structures of BET bromodomain inhibitors GSK525762 (1), JQ1 (2), OTX015 (3), and compound ET (4), featuring the methyltriazole
substructure fused to a 1,4-benzodiazepine.
Scheme 1. Original Racemic Synthesis for GSK525762 (1)
Scheme 2. Dihydropyridazinone Impurity 17 from Hydrazone 16 in the Original Synthesis
We envisioned that the replacement of hydrazine with
acethydrazide (AcNHNH2) could eliminate byproduct 17 and
shorten the synthesis. A new approach to the methyltriazolo-
[1,4]-benzodiazepine core was proposed (Scheme 3), starting
from lactam 14 or thiolactam 15. The use of acylhydrazides for
the synthesis of 1-alkyltriazole is known.5−10 The major
challenge would be the much lower reactivity of an
acylhydrazide, such as acethydrazide relative to hydrazine
which is often used in large excess. We found that the direct
reaction of acylhydrazides with lactams was impossible. Even
the more reactive thiolactams required extended heating at
high temperature, e.g., with refluxing benzyl alcohol in modest
B
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Scheme 3. Retrosynthesis of GSK525762 (1) via Reaction of Acethydrazide and the Activated Lactam or Thiolactam
Scheme 4. Preparation of Lactam 14 and Thiolactam 15 on Scale
yields by Hester et al.6 A common solution to the reactivity
issue is to activate the lactam or thiolactam, e.g., through O- or
S-methylation with methyl sulfate by Rigo et al.7a,b However,
they ran into the issue of O- vs N-selectivity, which was
resolved by two groups at Glaxo by use of trimethyloxonium
tetrafluoroborate on various substrates.7c,d Recently, a group at
Pfizer applied this method with triethyloxonium tetrafluor-
oborate in its synthesis of a PDE-IV inhibitor on a scale.7e
Another common mode of activation is through phosphor-
ylation with a wide variety of phosphorus reagents, e.g.,
bis(morpholino)phosphinyl chloride8a and chlorodiethylphos-
phate.8b Phosphorus oxychloride was also used to activate
lactams as imidoyl chlorides in the synthesis of benzodiaze-
pines.9
Most recently, mercury acetate was used in stoichiometric
amounts to activate thiolactams for reactions with acylhy-
drazides in large excess by Ciulli5 and Khan.10 This approach
did combine the typical three separate reactions (hydrazine
condensation, acetylation with a base, and cyclocondensation
with an acid as shown in Scheme 1 for the previous synthesis
of 1) in a one-pot process. Although we preferred not to use
the toxic mercury acetate on an industrial scale, their approach
of combining three reactions into one with the concurrent
activation of the thiolactam attracted our attention.
We herein report our findings in the execution of the
synthetic strategy shown in Scheme 3, assessing various means
of activating lactam 14 or thiolactam 15 for the formation of
acetylhydrazone 18 en route to methyltriazole 19. Our efforts
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Scheme 5. Activation of 14 and 15 under Typical Conditions
ultimately led to the discovery of a novel and unique activation
method and a 4-step synthesis of GSK525762 (1), delivering
over 52 kg of 1. Robust and efficient synthesis of 14 and 15
will also be described.
to below 1% by immediately cooling the reaction to 0 °C upon
completion. The slight erosion of enantiomeric purity from 14
to 15 was not a concern as the enantiomeric purity was
enhanced in the next step by crystallization.
With a good supply of 14 and 15, a variety of conditions
were tested to activate those two substrates for reactions with
acethydrazide to form acetylhydrazone 18 (Scheme 5).
Compound 18 was stable enough for isolation under mild
basic or neutral conditions. Cyclocondensation to methyl-
triazole 19 occurred very slowly at room temperature but was
faster with heating, particularly in the presence of an acid.
Our initial efforts of the activation focused on lactam 14,
following some known methods for activation of lactams as
their phosphates, alkyl imidates, and imidoyl halogens.5−10
Some of the attempted conditions were shown in Scheme 5.
Unfortunately, those approaches suffered from poor reactivity
of the lactam as well as the selectivity of O- vs N- for
phosphorylation and alkylation under basic conditions. For
example, treatment of 14 with a common base followed by
chlorodiethylphosphate gave a mixture of 22 and 23. Upon
addition of acethydrazide, only the phosphate 23 led to
acetylhydrazone 18, which further cyclocondensed to triazole
19. Phosphoramidate 22 remained intact under the conditions.
The highest amount of 19 by HPLC was about 50% achieved,
as shown. Metal hydride, alkoxides, and tertiary or aromatic
amines gave low conversions. For alkylation with methyl iodide
in the presence of potassium carbonate, only N-methyl product
24 was detected by LCMS, and it failed to give any triazole as
expected upon addition of acethydrazide.
RESULTS AND DISCUSSION
■
When the racemic synthesis for 7 and 8 as shown in Scheme 1
was adapted for the synthesis of lactam 14 and thiolactam 15
from (S)-6, up to 5% of racemization was observed. The use of
Lawesson’s reagent for the thionation was also not desirable
due to the extensive workup needed.11 Our new synthesis of
14 and 15, shown in Scheme 4 with the more readily available
carboxylic acid, was one step shorter and did not require any
extraction. In recent years, 1-cyano-2-ethoxy-2-oxoethyliden-
aminooxy)dimethylamino-morpholino-carbenium hexafluoro-
phosphate (COMU) emerged as a safe and efficient third
generation of a uronium-type peptide coupling reagent.12
The reaction of 5a and 20 activated by COMU was
exceptionally clean with hardly any racemization.13 The use of
bulky N,N-diisopropylethylamine was important to prevent the
premature loss of the Fmoc protection. Following the
formation of amide 21, triethylamine was added for Fmoc
deprotection and ring closure. The addition of methanol
followed by filtration provided 14 of 99.9% ee and in 82% yield
on 45 kg scale. Similarly, the thionation of 14 was greatly
simplified once Lawesson’s reagent was replaced by phospho-
rus pentasulfide and hexamethyldisiloxane.14 Thiolactam 15 of
98.6% ee was isolated in 81% yield on a 46.5 kg scale by direct
filtration of the quenched reaction. Thionation of the ester
carbonyl group did occur as a side reaction but was controlled
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Scheme 6. Oxidative Activation of 15 in the Presence of Acethydrazide for Facile Formation of Methyltriazole 19 and the
Control Experiments Supporting Proposed Reaction Pathway
We made significant efforts to make compounds 25−28 with
reagents such as phosphorus oxychloride, phosphorus
pentabromide, thionyl chloride, phosgene and triflic anhydride
with a base, as well as a variety of Lewis acids in stoichiometric
amounts. Generally, lactam 14 remained intact, and only 0−
10% of methyltriazole was observed by HPLC with the
concurrent or subsequent addition of acethydrazide. In
contrast, thiolactam 15 was converted to the desired methyl
thioimidate 29 efficiently under the same condition, and about
57% of the product was observed by HPLC upon treatment of
the crude 29 with acethydrazide. The extra transformation, as
well as the need to remove the base and alkylating reagent
prior to the addition of acethydrazide, made this approach
unattractive.
A breakthrough came when a reaction of 15 with
acethydrazide in the presence of copper acetate was
inadvertently left open to the air in the screening for activation
by Lewis acids. It was noted that methyltriazole 19 formed
faster than the reaction under nitrogen. It was postulated that
the oxygen served as an oxidant to activate the thiolactam.
Since air is generally not considered a safe source of oxygen in
the presence of a heated organic solvent, a screening of
oxidants was carried out, as shown in Scheme 6.
18. Furthermore, 18 underwent cyclocondensation to
methyltriazole 19 simultaneously prior to full depletion of
15. The cyclocondensation was slow with oxidants supplied
without an acid such as 30% hydrogen peroxide and cumene
hydroperoxide, but the ring closure was smooth and fast with
peracetic acid (35% or 39% solution in acetic acid).
Acetylhydrazone 18 could not be isolated under the acidic
condition due to the rapid conversion to the triazole, while it
was easily isolated from the previous route in which the
acetylation (with AcCl) of the hydrazone (from hydrazine)
was under the basic condition (with triethylamine, see Scheme
1). Notably, there was about 1−3% of lactam 14 observed,
while the input 15 was known to carry less than 0.5% of
residual 14 from the earlier thionation reaction. This prompted
us to investigate a potential intermediate formed from the
reaction of the thiolactam and the oxidant.
In a control experiment shown in Scheme 6, 15 was treated
with one equivalent of peracetic acid at room temperature.
Analysis by reverse phase HPLC (Method A) of a sample from
the eighth minute showed only 8.7% of 15 remaining at 2.46
min, and two new peaks at 2.29 and 2.78 min formed in 81.3%
and 7.3%, respectively. Analysis by LCMS identified the new
peaks to be sulfenic acid 30 and acetyl imidate 31, respectively
(see Supporting Information). Upon addition of acethydrazide,
both 30 and 31 converted to acetylhydrazone 18 rapidly with
concurrent ring closure to give methyltriazole 19. We believe
When a variety of oxidants were added to a mixture of 15
and acethydrazide in isopropanol at room temperature, 15 was
depleted rapidly with concurrent formation of acetylhydrazone
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Scheme 7. Synthesis of GSK525762 (1) on Scale via the Oxidative Activation of Thiolactam 15 by Peracetic Acid
that 31 formed from reaction of 30 and acetic acid.
Compounds analogous to 31 were not observed with hydrogen
peroxide and cumene oxide.
reactivity of moisture with 30 during filtration. Although we
proposed the structure of 30 as sulfenic (RS−OH) as shown in
Scheme 6, it could be the tautomeric hydrosulfinyl (RS(O)H).
In their review of sulfenic acids, Gupta and Carroll discussed
the tautomeric structures of sulfenic acids and concluded that
multiple studies supported the O-protonated form.16a LC-
HRMS conducted on the isolated mixture of 30 and 14
confirmed the molecular weight but did not differentiate
between the two. A general structural search on the conversion
of N-arylthioamides to thioimidates showed only a few hits,
e.g., with oxidation by sodium hypochloride (NaOCl) to a
sulfonyl16c and by 1-hydroxy-2,2,6,6-tetramethylpiperidine
(TEMPO) to a sulfenic ester of TEMPO.16d
For our objective of a practical and efficient synthesis of
GSK525762 (1), we chose the readily available and
inexpensive peracetic acid in acetic acid. Acetic acid also
catalyzed the cyclocondensation of acetylhydrazide 18 to the
triazole. This reaction has been scaled up multiple times in 50
to 2500 L scale with very high reproducibility. This step, as
well as the subsequent transformation for the synthesis of 1, is
shown in Scheme 7.
In a pilot plant preparative run using 40.1 kg of 15,
activation of the thiolactam by 35% peracetic acid in the
presence of acethydrazide went smoothly in 7 h to provide full
conversion to methyltriazole 19. We chose to heat the reaction
to about 50 °C so that there was only a minimum
accumulation of peracetic acid in the reaction vessel to avoid
any potential hazard with the peracid. Based on the profile
from reaction calorimetry, the oxidative activation of 15 to
sulfenic acid intermediate 30 (structure shown in Scheme 6)
was instantaneous under this set of conditions. Heating also
accelerated the reaction of 30 with acethydrazide and the ring
closure. After aqueous workup with sodium sulfite, 19 was
extracted into 2-methyltetrahydrofuran, and the solution after
concentration was treated with benzenesulfonic acid to give
the crystalline benzenesulfonic acid salt 19a in >99.9% ee and
99.8% purity by HPLC area in 75% yield. Isolation of salt 19a
was in higher yield than that of the free base due to the high
crystallinity of the salt.
In another control experiment, a mixture of 15 with
peracetic acid (Scheme 6) was held at room temperature in
the absence of acethydrazide. After 27 h, 77.7% of 14 was seen
by HPLC analysis, along with 11.6% of remainder sulfenic acid
30 and 1.8% of acetyl imidate 31. The formation of lactam 14,
seemingly a reversion from thiolactam 15, could be explained
by the reaction of sulfenic acid 30 and water. Water arose from
many oxidant solutions such as hydrogen peroxide and
peracetic acid.15 Fortunately, the hydrolysis of 30 and 31
was a much slower process than the displacement of the
pendant groups by acethydrazide. In a typical reaction with
acethydrazide, premixed into the reaction mixture prior to the
addition of an oxidant and even in the presence of a large
amount of water from 30% aqueous hydrogen peroxide, 14 was
observed at <5%, and it could be efficiently purged in the
subsequent crystallization.
The reaction of thiolactam 15 and acetic acid, in the absence
of peracetic acid, did not give acetyl imidate 31 at room
temperature, supporting the role of peracetic acid in the
activation of the thiolactam. It should be pointed out that the
attempted activation of lactam 14 by those same oxidants
shown in Scheme 6 led to only a negligible amount (0−2%) of
products 18 and 19; we found 14 mostly intact even on
heating. Additionally, the direct reaction of thiolactam 15 and
acethydrazide to form 19 required high heating in n-butanol,
similar to the literature reports.6 The reactions under those
conditions were incomplete and produced impurities from
extensive degradation and racemization.
The activation of thiolactam by oxidation for nucleophilic
displacement was a novel approach to the best of our
knowledge, and it offered much potential for other thioamides
and nucleophiles other than acethydrazide. There is only
limited reporting on sulfenic acids and their reactivities.16
Generally, sulfenic acids were reported as too reactive to be
isolated.16a,b Indeed, when trying to isolate 30 by cooling and
filtration of the resultant yellow solids upon addition of
peracetic acid to 15, the filtered cake was hygroscopic and
quickly turned darker in color. Sulfenic acid 30 was isolated in
68% purity by HPLC, along with 23% of 14, arising from the
Conversion of the methyl ester 19a to ethyl amide 1 in a
single step was achieved by 70% aqueous ethylamine.
Methanol was used to facilitate the initial dissolution of 19a,
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to give amide 21, with ≤3% of 5 remaining by HPLC Method A (5 @
2.30 min, 21 @2.89 min). To the mixture was then added
triethylamine (53.5 kg, 529 mol). The reaction was stirred at 50 °C
for an additional 8 h to effect Fmoc deprotection and ring closure to
give lactam 14, with ≤1% of 21 remaining by HPLC Method A (21
without Fmoc @ 1.91 min, 14 @ 2.27 min). The slurry was cooled to
20 °C and treated with methanol (215 kg). After being aged for 1 h,
the mixture was filtered via a filter drier. The filtered cake was washed
three times with methanol (180 kg) and dried under about 25 Torr
for 6 h to give 14 (46.2 kg, 82%) as an off-white solid: AUC 99.6% by
HPLC Method A, ee > 99.9% by the chiral method below. Mp:
203.8−207.0 °C. [α]2D1 +114.5 (c 0.922, DMSO). 1H NMR (400
MHz, CDCl3): δ 8.50 (br s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.36 (d, J =
8.6 Hz, 2H), 7.12 (s, 1H), 6.76 (s, 1H), 4.18 (t, J = 7.1 Hz, 1H), 3.75
(s, 3H), 3.74 (s, 3H), 3.39 (dd, J = 16.8, 7.2 Hz, 1H), 3.20 (dd, J =
16.8, 6.7 Hz, 1H). 13C{H} NMR (75 MHz, DMSO-d6): δ 171.5,
169.4, 166.6, 154.2, 137.1, 135.2, 132.6, 131.0, 128.3, 126.8, 122.9,
119.1, 113.4, 60.3, 55.5, 51.3, 35.9. HRMS (ESI): m/z calcd for
C19H18ClN2O4 (M + H)+, 373.0950; found, 373.0951
and the small amount of methanol did not appreciably delay
the amide formation. A small amount of a carboxylic acid
byproduct from the hydrolysis of the ester moiety of 19 was
purged in the extractive workup. The dissolved crude free base
1 from the extraction was solvent exchanged into MeCN, from
which the highly crystalline 1:1 acetonitrile solvate 1a in
>99.9% ee was isolated in 82% yield on a 78.2 kg scale.17
CONCLUSION
■
A novel activation of thiolactam 15 by oxidation was developed
for the preparation of methyltriazolo[1,4]benzodiazepine 19 in
a single step. A sulfenic acid (RS−OH, 30) was proposed as
the activated intermediate, which underwent substitution
readily with acethydrazide, followed by the acid-catalyzed
cyclocondensation in situ. The conditions for the methyl-
triazole formation were mild and free of racemization of the
sensitive stereocenter. The method, superior to the known
methods to form alkyltriazoles, should be applicable for the
synthesis of other triazoles from thiolactams and acylhydra-
zines.
Chiral HPLC: Daicel CHIRALPAK IC (150 × 4.6 mm, 5 μm), 1.0
mL/min, detection @233 nm, 30 °C. Eluents: 70:30 (v/v) heptane/
ethanol. Compound 14 @ 6.15 min, ent-14 (d-enantiomer) @ 7.85
min.
A version of the peracetic acid method was scaled up to 40
kg as a part of the new route for the synthesis of BET inhibitor
molibresib (GSK525762, 1). The concise four-step synthesis
starting from commercially available 2-amino-5-methoxy-
phenyl)(4-chlorophenyl)methanone (5a) provided 52 kg of
1 of 99.9% ee in overall 41% yield.
Methyl (S)-2-(5-(4-Chlorophenyl)-7-methoxy-2-thioxo-2,3-dihy-
dro-1H-benzo[e][1,4]diazepin-3-yl)acetate (15). To a 2500 L
reactor were successively added MeCN (86 kg), lactam 14 (46.5
kg, 121 mol), phosphorus pentasulfide (14.0 kg, 60.4 mol) and
hexamethyldisiloxane (35.3 kg, 217 mol), followed by additional
acetonitrile (70 kg) to rinse down the solids. A thick yellow slurry
formed at room temperature. After being stirred vigorously for 10
min, the mixture was heated to 60 °C and stirred for about 4 h. The
reaction mixture became a red thin slurry, with ≤3% of 14 remaining
by HPLC Method A (14 @ 2.27 min, 15 @2.42 min). The reaction
was cooled to 0 °C and quenched over about 40 min with 0.61 M
aqueous solution of potassium carbonate (405 L, 245 mol) to keep
the temperature below 5 °C. After being stirred at 0 °C for 1 h, the
mixture was treated with isopropanol (142 kg) and stirred for an
additional 1 h. The slurry was filtered via a filter drier. The filtered
cake was successively washed with water (47 L) and with 1:1 water/i-
PrOH (2 × 47 L) and dried at 50 °C under about 25 Torr for 8 h to
give 15 (42.0 kg, 81%) as a yellow solid: AUC 96.6% by HPLC
Method A, ee 98.6% by the chiral method below. Mp: 189.1−191.5
EXPERIMENTAL SECTION
■
General Procedures. All reactions were run under nitrogen.
Unless otherwise specified, concentration by rotary evaporation or
distillation was carried out under house vacuum of 12−50 Torr.
Heating was provided by a steam-heated silicon heat transfer fluid in
the pilot plant for all of the reactions on a kilogram scale. All other
reactions were heated with an oil bath. Melting points were measured
in Mettler Toledo MP 90 Melting Point System at 3 °C/min ramp,
and the results were not corrected. The optical rotations were
recorded in JASCO P-2000 Polarimeter. All NMR spectra were
acquired at ambient temperature on a Bruker 400 MHz spectrometer.
Solvents and frequencies for specific data acquisitions are noted for
each case in the following sections. Chemical shifts were calibrated
relative to residual protio solvent (1H and 13C). Data were processed
using ACD Spectrus. HPLC analysis was performed on Agilent 1260
or 1290 series instruments with diode array detectors, though analysis
was typically done with traces from a single wavelength. HRMS (m/z)
was measured using a Thermo Scientific Orbitrap Eclipse mass
spectrometer equipped with a heated electrospray ionization (HESI)
ion source.
°C. [α]2D1 +76.1 (c 1.10, MeOH). H NMR (400 MHz, CDCl3): δ
1
10.24 (br s, 1H), 7.49 (m, 2H), 7.35 (m, 2H), 7.21 (m, 1H), 7.13 (m,
1H), 6.78 (d, J = 2.2 Hz, 1H), 4.39 (dd, J = 7.0, 6.8 Hz, 1H), 3.76 (s,
3H), 3.74 (s, 3H), 3.66 (m, 1H), 3.39 (dd, J = 16.8, 7.0 Hz, 1H).
13C{H} NMR (75 MHz, CDCl3): δ 199.9, 172.2, 167.9, 156.3, 137.0,
136.7, 132.7, 131.3, 129.4, 128.5, 122.7, 119.15, 114.6, 63.8, 55.8,
51.8, 39.5. HRMS: (M + H)+ m/z calcd for C19H18ClN2O3S,
389.0721; found, 389.0723.
Chiral HPLC: Chiralcel OJ-RH (150 mm × 4.6 mm, 5 μm), 1.0
mL/min, uncontrolled temperature (20−25 °C), detection @220 nm.
Eluents: water 0.05% TFA (A), MeCN 0.05% TFA (B). 60:40 A/B.
Compound 15 @ 16.55 min, ent-15 (d-enantiomer) @ 18.75 min.
Methyl 2-((4S)-6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H-
benzo[f ][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetate, Benzene-
sulfonic Acid Salt (19a). To a 2500 L reactor were successively
added isopropanol (167 kg), 95 wt % acethydrazide (12.8 kg, 165
mol) and thiolactam 15 (40.1 kg, 103 mol), followed by additional
isopropanol (96 kg) to wash down the solids. The resulting yellow
slurry was stirred at 60 rpm and heated to 50 °C, followed by the
addition of peracetic acid (∼35 wt % in HOAc, 26.9 kg, 124 mol)
over about 45 min. The addition was exothermic, and the temperature
was kept at 50−60 °C throughout the addition. The reaction was
stirred at 50 °C for 7 h, with ≤3% of remaining uncyclized
acetylhydrazone 18 by HPLC Method A (18 @ 2.03 min, 15 @2.42
min, and 19 @2.21 min). The slurry was cooled to 15 °C and
quenched with 10 wt % (∼1 M) aqueous sodium bisulfite (40.1 kg,
38.6 mol) over about 30 min. An aliquot was tested with a strip of KI/
starch paper to ensure a negative result (white color for the absence of
Generic HPLC Method A: Zorbax SB-C18 (3.0 mm × 50 mm, 1.8
μm), 1.5 mL/min, detection @220 nm, 60 °C. Eluents: 0.05% v/v
TFA in water (A), 0.05% v/v TFA in MeCN (B). 100% A 0 min,
100% B 2.71 min, hold 0.29 min. Generic HPLC Method B: Luna
C18 (2.0 mm × 50 mm, 3.0 μm), 1.0 mL/min, detection @220 nm,
40 °C. Eluents: 0.05% v/v TFA in water (A), 0.05% v/v TFA in
MeCN (B). Gradient: 0−95% B over 8 min. Other HPLC methods,
including one achiral and four chiral methods, are listed under the
procedure for individual reactions.
Methyl (S)-2-(5-(4-Chlorophenyl)-7-methoxy-2-oxo-2,3-dihydro-
1H-benzo[e][1,4]diazepin-3-yl)acetate (14). To a 2500 L reactor
were successively added ethyl acetate (170 kg), (S)-aspartic acid 20
(61.2 kg, 166 mol), COMU (77.9 kg, 182 mol), and amino
benzophenone 5a (HCl salt, 45.0 kg, 151 mol), followed by additional
ethyl acetate (75 kg) to wash down the solids. A thick but well-stirred
slurry formed. The mixture was stirred at 60 rpm, and N,N-
diisopropylethylamine (41.5 kg, 321 mol) was added. A nearly
homogeneous solution formed from the slight exotherm of the
addition. The reaction mixture was heated to 50 °C and stirred for 4 h
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residual oxidant). If the paper was purple, additional sodium bisulfite
was added. The heterogeneous mixture was then distilled under a
house vacuum (30−100 Torr) to about 180 L at an external
temperature of 50−55 °C. After the distillation, the mixture was
cooled to 25 °C and treated with 2-methyltetrahydrofuran (345 kg)
and water (200 kg). The resulting biphasic mixture was stirred for 30
min at room temperature and filtered via a two-stage in-line 0.2-μm
filter to remove any sulfur-containing particles. An additional 2-
methyltetrahydrofuran (80.3 kg) was used to rinse the reactor and
added to the in-line filtration. The biphasic mixture was settled for 1 h
before the phase split. The organic layer was distilled at atmospheric
pressure down to about 245 L to give 19 as a solution in 2-
methyltetrahydrofuran.
methyltetrahydrafuran. The heating during this part of the workup
was designed to avoid emulsions otherwise observed at room
temperature.
Solvent swap from the 2-methyltetrahydrofuran to acetonitrile was
carried out by the distillation of the solution under reduced pressure
(∼100 Torr) to about 250 L, followed by dilution with acetonitrile
(300 L) and further distillation to about 300 L. This operation was
repeated twice whereupon GSK525762 (1) crystallized as the
acetonitrile solvate (1a). After being cooled to 0−5 °C over 1 h,
the slurry was aged for 1 h and filtered via a filter dryer. The reactor
was rinsed with acetonitrile (250 L, precooled to 0 °C). The filtered
cake was washed with the rinse and dried at 30 °C under about 100
Torr and a stream of nitrogen for 4 h to give 1a (52.4 kg, 82%) of
AUC > 99.9% by achiral HPLC method below and >99.9% ee by the
chiral HPLC method below as a white crystalline solid. Mp: 118.9−
120.3 °C. [α]2D1 +87.0 (c 1.41, MeOH). 1H NMR (400 MHz, CDCl3)
1a: δ 7.48 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.9 Hz, 1H), 7.34 (d, J =
8.9 Hz, 2H), 7.21 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 2.9 Hz, 1H),
6.69 (br s, 1H), 4.63 (t, J = 7.1 Hz, 1H), 3.80 (s, 3H), 3.50 (dd, J =
14.1, 7.3 Hz, 1H), 3.20−3.43 (m, 3H), 2.62 (s, 3H), 2.01 (s, 2H),
1.19 (t, J = 7.3 Hz, 3H). 13C{H} NMR (75 MHz, DMSO-d6): δ
169.2, 165.5, 157.3, 155.8, 150.6, 137.2, 135.4, 131.0, 129.3, 128.2,
126.4, 125.5, 117.8, 115.1, 55.8, 53.3, 37.6, 33.4, 14.8, 11.5. HRMS
(ESI): m/z calcd for C12H20N (MH+) for C22H23ClN5O2, 424.1535;
found, 424.1537.
The concentrate above was heated to 35 °C, and 25.3 wt/wt %
benzenesulfonic acid solution (34.9 kg, 55.8 mol) in 2-methylte-
trahydrofuran was added over about 1 h. The solution was then
seeded with 19a (40 g, 0.001 wt of the input 15) as a slurry in 2-
methyltetrahydrofuran (400 mL). Crystallization occurred within
minutes at 35 °C after seeding. An additional 25.3 wt/wt %
benzenesulfonic acid solution (34.9 kg, 55.8 mol) was added over
about 1 h. The resultant slurry was cooled to 0 °C at about 1.0 °C/
min rate and stirred for 12 h. The mixture was filtered via a filter drier.
The cake was washed with 2-methyltetrahydrofuran (2 × 68.2 kg) and
dried at 70 °C under about 25 Torr to give the benzenesulfonic acid
salt 19a (43.8 kg, 75%) as an off-white crystalline solid: AUC 99.9%
by HPLC Method A, ee > 99.9% by the chiral HPLC method below.
Compound 1 (parent, from chromatographic purification of the
Mp: 124.6−127.0 °C. [α]2D1 +68.3 (c 1.44, MeOH). H NMR (400
crude): [α]2D1 +90.6 (c 1.43, MeOH) (lit.2a [α]2D0 +88.1 (c 1.00,
1
1
MHz, CDCl3) 19a: δ 7.89 (d, J = 9.0 Hz, 1H), 7.76 (m, 3H), 7.49 (d,
J = 8.3 Hz, 2H), 7.30−7.33 (m, 4H), 7.25 (dd, J = 8.9, 2.8 Hz, 1H),
6.90 (s, 1H), 4.67 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.45−3.65 (m,
2H), 3,09 (s, 3 H). 13C{H} NMR (75 MHz, DMSO-d6): δ 170.6,
166.6, 158.5, 155.0, 152.4, 148.0, 136.7, 135.7, 131.4, 129.8, 128.5,
128.2, 127.6, 126.2, 125.5, 124.3, 117.9, 115.8, 56.0, 52.2, 51.7, 35.8,
11.2. HRMS: (M + H)+ m/z calcd for C21H20ClN4O3, 411.1218;
found, 411.1220.
MeOH)). H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.0 Hz, 2H),
7.39 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.21 (dd, J = 8.9,
2.9 Hz, 1H), 6.85 (d, J = 2.9 Hz, 1H), 6.69 (br s, 1H), 4.63 (t, J = 7.1
Hz, 1H), 3.80 (s, 3H), 3.50 (dd, J = 14.1, 7.3 Hz, 1H), 3.20−3.43 (m,
3H), 2.62 (s, 3H), 1.19 (t, J = 7.3 Hz, 3H). 13C{H} NMR (75 MHz,
DMSO-d6): δ 169.2, 165.5, 157.4, 155.8, 150.6, 137.3, 135.4, 131.0,
129.3, 128.2, 126.4, 125.5, 117.8, 115.1, 55.8, 53.3, 37.6, 33.4, 14.8,
11.5.
Compound 19 (free base, from chromatographic purification of the
crude): [α]2D1 +78.1 (c 1.42, MeOH). 1H NMR (400 MHz, CDCl3): δ
7.50 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 8.6 Hz,
2H), 7.22 (dd, J = 8.9, 2.8 Hz, 1H), 6.89 (d, J = 2.9 Hz, 1H), 4.61
(dd, J = 7.8, 6.4 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.62 (m, 2H),
2.62 (s, 3 H). 13C{H} NMR (75 MHz, DMSO-d6): δ 171.1, 165.8,
157.4, 155.3, 150.8, 137.1, 135.4, 131.0, 129.2, 128.2, 126.3, 125.5,
117.8, 115.3, 55.8, 52.8, 51.5, 36.2, 11.4.
Chiral HPLC: Chiralcel OJ-RH (150 × 4.6 mm, 5 μm), 1.0 mL/
min, 50 °C, detection @229 nm. Eluents: water 0.05% TFA (A),
MeCN 0.05% TFA (B). 80:20 A/B. Compound 19 @ 20.50 min, ent-
19 (d-enantiomer) @ 23.70 min.
2-((4S)-6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f ]-
[1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide, Acetoni-
trile Solvate (1a). To a 2500 L reactor were successively added
methanol (68 L) and 19a (78.2 kg, 137 mol) to form a solution,
followed by additional methanol (10.2 L) to wash down the solids.
After being cooled to 10−15 °C, the solution was treated with 70 wt
% aqueous ethylamine (190 kg, 2938 mol), which was precooled to 5
°C. The mixture was stirred at 60 rpm at room temperature for 20 h,
with ≤0.2% of the remaining 19 by HPLC (19 @ 2.21 min, 1 @1.85
min). The reaction mixture was diluted with 2-methyltetrahydrofuran
(781 L) and cooled to 10 °C. The mixture was treated with 25 vol %
aqueous acetic acid solution (604 L, 2638 mol), which was precooled
to 5−10 °C. The addition was carried over 30 min to keep the
temperature below 25 °C, followed by a line rinse with water (30 L).
The aqueous layer had a pH ≥ 8−9, and this removed a small amount
of a carboxylic acid byproduct formed from hydrolysis of 19 during
the reaction. The layers were separated, and the organic layer was
further basified with 5 wt % aqueous sodium bicarbonate solution
(391 L, 233 mol). The biphasic mixture was heated to 45 °C and
stirred for 10 min. The layers were separated at 45 °C, and the organic
layer was treated with water (234 L) at 45 °C. The biphasic mixture
was stirred at this temperature for 10 min. The layers were separated
at 45 °C to obtain crude GSK525762 free base (1) as a solution in 2-
Achiral HPLC: Zorbax Eclipse Plus C-18 (50 mm × 4.6 mm, 1.8
μm), 1.5 mL/min, detection @210 nm, 40 °C. Eluents: water 0.1%
H3PO4 (A), MeCN (B). 70% A 0 min, 0% A 4 min, hold 2 min.
Compound 19 @ 2.21 min, 1 @1.85 min.
Chiral HPLC: Daicel CHIRALPAK IC (150 mm × 4.6 mm, 5 μm),
1.5 mL/min, detection @240 nm, 15 °C. Eluents: 500:500:1:1 water/
MeCN/DMF/H3PO4. Compound 1 @ 6.7 min, ent-1 (d-enantiomer)
@ 4.5 min.
Methyl (S)-2-(5-(4-Chlorophenyl)-2-(hydroxythio)-7-methoxy-
3H-benzo[e][1,4]diazepin-3-yl)acetate (30). Experiment A for
Characterization by LCMS. To thiolactam 15 (2.00 g, 5.14 mmol)
in a 50 mL flask was added isopropanol (16 mL), followed by 39%
peracetic acid in acetic acid (0.88 mL, 5.14 mmol) at ambient
temperature over about 2 min. The slurry became thinner and
changed from yellow to orange color. The mixture was sampled after
8 min for HPLC and LCMS analysis. See the HPLC (Method A)
chromatogram in Scheme 6 and the LCMS information in Supporting
Information. The HPLC showed only 8.7% of 15 left at 2.46 min,
with the formation of 81.3% of activated sulfenic acid intermediate 30
at 2.29 min, along with 7.3% of acetyl imidate 31 at 2.78 min. The
structure assignment for 30 and 31 was solely based on LCMS. The
order of retention times in the reverse HPLC and LCMS
corroborated with the estimated polarity of those compounds relative
to 15. After the first sample, additional 39% peracetic acid (0.18 mL,
1.05 mmol) was added. The mixture was stirred for 5 min and the
second sample was taken for HPLC, which showed only 0.7% of 15
left. At that time, acethydrazide (0.682 g, 8.74 mmol) was added in
one portion as a solid, and the reaction was heated to 50 °C. After 1
and 6 h, HPLC showed only 0.7% and 0.2% of the activated
intermediate 30 left, respectively, with triazole 19 forming
concurrently.
Experiment B for Isolation and Characterization by HRMS. To
15 (5.00 g, 12.9 mmol) in a 100 mL flask was added isopropanol (40
mL). The yellow slurry was heated to 50 °C and stirred for 10 min to
maximize any potential dissolution. After being cooled to room
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temperature, the mixture was treated with 39% peracetic acid (2.62
mL, 15.4 mmol) dropwise over about 4 min. During the addition, the
slurry turned into a red and almost homogeneous mixture. The
mixture was stirred for 10 min at room temperature and sampled for
HPLC (Method A), which showed 68% of the sulfenic acid product
30 at 2.29 min and 25% of lactam 14 at 2.27 min. We believe that 14
formed from the hydrolysis of 30 (water brought in the peracetic acid
solution, see ref 15) in the absence of acethydrazide, as well as from
analysis with water in the eluting mobile phase. The red mixture was
cooled with an ice bath which immediately generated yellow solids.
Filtration followed by a wash with isopropanol (10 mL) produced a
yellow cake. However, the filtered cake turned darker within a few
minutes while under a vacuum for further drying. The cake was
apparently hygroscopic and picked up moisture in the air and
underwent hydrolysis to give lactam 14. The solid was only partially
transferrable to a bottle for further drying in the oven under nitrogen.
Analysis by HPLC showed 68% of 30 and 23% of 14. Analysis by
HRMS confirmed the exact mass of 30. HRMS (ESI): m/z calcd for
C12H20N (MH+) for C19H18ClN2O4S, 405.0670; found, 405.0672.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
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AUTHOR INFORMATION
Corresponding Author
Shiping Xie − Product Development and Supply,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States; orcid.org/0000-0002-6512-8254;
Email: shiping.x.xie@gsk.com
■
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COMU: A safer and more effective replacement for benzotriazole-
Authors
Greg A. Erickson − Product Development and Supply,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States
Mark A. Hatcher − Product Development and Supply,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States
Michel Journet − Product Development and Supply,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States
John A. Kowalski − Product Development and Supply,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States
Tom C. Lovelace − Product Development and Supply,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States
Christopher J. Pink − Product Development and Supply,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00563
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mark Bokhart for acquiring the HRMS data and
Sean Sisk and the staff in the plant for their support in the scale
up of the processes.
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based uronium coupling reagents. Chem. - Eur. J. 2009, 15, 9404−
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scale through a Sugasawa reaction. See: Sugasawa, T.; Toyoda, T.;
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(17) The benzenesulfonic acid salt of 1 was also known to be
crystalline and could be prepared from the acetonitrile solvate 1a.
J
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