Process Development and GMP Production of a Potent NAE Inhibitor Pevonedistat

Article abstract of DOI:10.1021/acs.oprd.5b00209

A practical synthesis of a novel NEDD8-activating enzyme (NAE) inhibitor pevonedistat (MLN4924) is described. Key steps include an enantioselective synthesis of an amino-diol cyclopentane intermediate containing three chiral centers and a novel, regiosele

Full text of DOI:10.1021/acs.oprd.5b00209

Article
pubs.acs.org/OPRD
Process Development and GMP Production of a Potent NAE Inhibitor
Pevonedistat
Ian Armitage, Eric L. Elliott, Frederick Hicks, Marianne Langston, Ashley McCarron,
Quentin J. McCubbin, Erin O’Brien, Matt Stirling, and Lei Zhu*
Chemical Development Laboratories, Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited, 40
Landsdowne Street, Cambridge, Massachusetts 02139, United States
ABSTRACT: A practical synthesis of a novel NEDD8-activating enzyme (NAE) inhibitor pevonedistat (MLN4924) is
described. Key steps include an enantioselective synthesis of an amino-diol cyclopentane intermediate containing three chiral
centers and a novel, regioselective sulfamoylation using N-(tert-butoxycarbonyl)-N-[(triethylenediammonium)sulfonyl]azanide.
The linear process, involving six solid isolations, has been carried out in multiple cGMP productions on 15−30 kg scale to
produce pevonedistat in 98% (a/a) chemical purity and 25% overall yield.
installation of the chemically labile3 sulfamoyl group and
coupling of commercially available aminoindane 6 with 4-
INTRODUCTION
(((1S,2S,4R)-4-{4-[(S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-
pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl
sulfamate hydrochloride) (pevonedistat, Figure 1), a novel
■
chloropyrrolopyrimidine 3, derived from aminodiol 4 and
commercially available aldehyde 5.4 Development of a scalable
route toward the cyclopentane amine diol intermediate 4 and
optimization of the chemically inefficient sulfamoylation were
therefore key to enabling a scalable synthesis of pevonedistat
via the proposed route and are the primary focus of this paper.
Synthesis of Amino Diol 4. Route scouting for alternative
routes to 4 lead to two approaches which were chosen for more
detailed evaluation for scale-up feasibility. The first approach
utilized the Sharpless asymmetric epoxidation of 11 followed by
Figure 1.
regioselective reduction to install the desired stereo config-
uration of the primary and secondary alcohols (13, Scheme 3).
NEDD8-activating enzyme (NAE) inhibitor, has demonstrated
in vitro cytotoxic activity against a variety of human
malignancies and is currently being developed by Takeda
Pharmaceuticals Company Limited as a clinical candidate for
the treatment of cancer.1 The five-membered ring, consisting of
three chiral centers and an acid/base sensitive terminal
sulfamoyl group, presented considerable challenges for the
development of a practical and scalable synthesis of
pevonedistat.
The original Discovery synthesis toward pevonedistat
involved 20+ linear steps and multiple chromatographic
purifications (Scheme 1). More than half of the chemical
transformations in the synthesis were carried out to construct
the chiral five-member ring. Poor efficiency resulted from a low
yielding resolution, removal of an extra chiral hydroxyl group,
and installation of a ketal protecting group. Furthermore, the
late stage terminal sulfamoylation on the primary hydroxyl
group was poorly selective and low yielding.2 As such, the
Discovery route was not considered amendable for large-scale
cGMP productions. This report describes the efforts leading to
the current manufacturing process for the synthesis of
pevonedistat.
Allyl alcohol 11, a key intermediate for asymmetric
epoxidation, was prepared according to literature references
with a different amine protecting group.5 The use of trityl
group instead of the other protecting groups reported in the
references was aimed at better stereo control over the
epoxidation step. Reaction of commercially available chiral
lactam 7 with SOCl2 in MeOH afforded 8 in >95% yield after
precipitation with MTBE. Trityl protection of 8 provided 9 in
quantitative yield, and the resultant DCM product solution was
used in the next step without isolation. Double bond migration
promoted by DBU proceeded smoothly, and residual DBU was
removed by extractive aqueous work-up. Solvent exchange to
toluene allowed telescoping of 10 to the subsequent DIBAL-H
reduction. Following aqueous work up, the desired product 11
was obtained by removal of toluene under reduced pressure,
and the resulting crude oil was redissolved in DCM prior to use
in the Sharpless epoxidation. The standard Sharpless
epoxidation conditions, utilizing (+)-diethyl L-tartrate, pro-
duced the desired stereoisomer 12 exclusively,6 and the product
was isolated in >80% yield after purification via column
chromatography. The regioselectivity of the subsequent
reductive epoxide ring opening was an obstacle for this route.
Overall Process Development Strategy. The alternate
approach envisioned to support cGMP production of
pevonedistat is displayed in the retrosynthesis shown in
Scheme 2. Key hallmarks of this approach involved end-game
Received: June 25, 2015
© XXXX American Chemical Society
A
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Scheme 1. Original Discovery Synthesis of Pevonedistat
Scheme 2. Retrosynthetic Analysis of Compound 1 (Free Base of Pevonedistat)
Previous literature suggested that use of Red-Al would provide
the desired product 13 in high regioselectivity.7 Unfortunately,
no desired reaction occurred with 12 under the Red-Al
conditions. A few other reducing reagents tested, such as
borane−THF, borane−DMSO, LiAlH4, and NaBH4, resulted in
mixtures of 13 and 14, favoring the formation of 14. This step
was not further optimized and the mixture of 13 and 14 (1:1.3),
resulting from the reaction with borane−THF as reducing
reagent, was used to assess the later steps. Attempts to separate
13 from 14 by column chromatography proved difficult. In
order to obtain pure 13, a protecting group strategy was
employed to take advantage of the differential reactivity of the
primary alcohol in the less-hindered 1,3-diol system of 13
compared to the 1,2-diol of 14. The use of 1.0 equiv of
triisopropylsilyl chloride (TIPSCl) based on the amount of 13
in the mixture showed exclusive reactivity with 13 over 14 in
B
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Scheme 3. Synthesis of Amino Diol 4 though Sharpless Epoxidation
Scheme 4. Current Manufacturing Process of Amino-Diol Intermediate 4-HBr
DCM at ambient temperature. However, separation of silylated
13 from unprotected 14 still required column chromatography.
Removal of the silyl protecting group was achieved with TBAF
affording 16 with 97% (a/a) purity by HPLC after column
chromatography. The final removal of the trityl group was
achieved via hydrogenolysis, to provide the desired chiral
building block 4 in 70% isolated yield. While the route depicted
in Scheme 3 proved successful in delivering 500 g of 4, low
yields in the late sequence and multiple chromatographic
purifications highlighted that significant process improvements
would be required for larger scale production.
Following the development of the Sharpless epoxidation
route, a synthesis of 4 utilizing commercially available (1R,4R)-
4-tertbutoxycarbonylamino-cyclopent-2-enecarboxylic acid
(17) was explored based on a known stereospecific
lactonization of cyclic or noncyclic α,β-unsaturated carboxylic
acid (Scheme 4).8 Bromolactonization of 17 afforded a single
stereo isomer bromolactone 18. This transformation initially
involved tetrabutylammonium hydroxide as base and DCM as
solvent. Upon completion of reaction, a solvent exchange to
ethyl acetate facilitated the extraction of the tetrabutylammo-
nium bromide byproduct into the aqueous layer. The
concentration of the ethyl acetate layer afforded 18, as a
beige solid, which required recrystallization. To avoid the time-
consuming solvent exchange and solvent removal during
isolation, efforts were later made to identify a reaction system
that would allow direct isolation. Building on the knowledge
that the starting material 17 and bromolactone 18 had very low
solubility in water, a screen was designed to target additional
solvents and bases that would enhance the solubility of 17 while
still acting as an antisolvent for bromolactone 18. A cosolvent
system of 30% (v/v) 1,2-dimethoxyethane (DME) in water
with pyridine as the base offered sufficient solubility of 17 while
allowing for precipitation of 18 from the reaction medium and
easy isolation by filtration. This homogeneous aqueous/organic
system also offered a cleaner purity profile (>97% a/a by
HPLC) for the bromolactone 18. Major byproducts, including
the pyridinium hydrobromide salt generated during the
reaction, were readily removed during filtration and washing.
Reductive ring opening of 18 with lithium borohydride,
followed by Boc-deprotection of 19 under acidic conditions
afforded 20. The Boc-deprotection step to intermediate 20 was
modified by substituting hydrogen chloride with hydrogen
bromide to eliminate the potential of generating mixed HCl
and HBr salts. Both intermediates 19 and 20 are hygroscopic
solids and were not isolated. Hydrogenation of telescoped
intermediate 20 from 18 with palladium on carbon under basic
conditions afforded amino-diol 4-HBr in good yield as the
hydrogen bromide salt. Solvent exchange to isopropyl alcohol
resulted in spontaneous crystallization of compound 4-HBr,
which was isolated as a white solid by filtration in 80% yield.
The success of this route mainly relies on the stereospecific
C
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Scheme 5. Cyclization and Coupling to 2
Scheme 6. Sulfamoylation Chemistry with Reagents 22 and 23
Scheme 7. Burgess-Type Reagent Synthesis
bromolactonization of 17 and clearly demonstrated superiority
over the previously described epoxidation approach to 4. The
optimized manufacturing process of 4-HBr was successfully
used to generate 60 kg of intermediate 4-HBr in a single batch
with >95% (a/a) purity by HPLC.
completion, crystallization is induced by cooling and addition
of MeCN/water as antisolvent, affording 2 in ca. 90% yield and
>99% (a/a) purity.
Sulfamoylation. Sulfamoylation of 2 presented another
significant challenge for the synthesis of pevonedistat (Scheme
2). Both primary and secondary alcohols on 2 were similarly
reactive toward sulfamoylation reagents 22 and 2310 (Scheme
6) used by Discovery, and a mixture of the desired product 1
with regioisomer (1′) and bis-sulfamoylated byproduct (24)
was produced, requiring purification of 1 by chromatography.
Both approaches posed challenges to overcome with regards to
efficiency10a,11 and safety11a in order to achieve successful scale-
up. Sulfamoylation of mono silyl protected 2 on the secondary
alcohol was also explored. However, poor selectivity during
mono deprotection and necessary chromatographic purification
made this approach less preferred for scale-up (Scheme 6).
Development of a regioselective sulfamoylation process
began with the replacement of sulfamoyl chloride by tert-
butyl carboxylsulfamoyl chloride in the hopes that the bulky
tert-butyl group should provide selectivity in favor of the
primary alcohol. tert-Butyl carboxylsulfamoyl chloride 25 was
readily prepared by reacting tert-butanol with chlorosulfonyl
Cyclization and Coupling. Formation of pyrrolo-[2,3]-
pyrimidine compounds, similar to 3, by coupling of amines with
acetal 21 is known in the literature.9 Diol 4 (or 4-HBr)
underwent the same reaction smoothly with 21. In the presence
of triethylamine, the amino group on intermediate 4 (or 4-
HBr) reacted with 21 to effect rapid chloride displacement and
spontaneous ring closure to afford 3. Further development
identified that more stable aldehyde 5, also commercially
available, provided a better reaction profile under the same
reaction conditions (Scheme 5). After reaction completion,
direct precipitation of the product by the addition of water
provided 3 in 80% yield with >98% (a/a) purity. The coupling
of 6 and 3 required high energy for a fast reaction rate.
Development efforts were focused on pressured reactions with
various temperatures and pressure levels. Currently the reaction
is performed at approximately 130 °C at 80−120 psi with 2-
butanol as solvent and DIPEA as a base. Upon reaction
D
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Scheme 8. Base Screen for tBu/Tertiary Amine Combinations for Novel Burgess-Type Reagents
isocyanate12 and was directly reacted with 2 in the presence of
an amine base such as triethylamine (Scheme 7). Mixing alkyl
carboxylsulfamoyl chloride with tertiary amines generates inner
salts, commonly known as Burgess-type reagents.13 Although
widely used in synthetic chemistry,12,14 the isolation and
purification of Burgess-type compounds is not trivial.14d
Separation of inner salts from amino hydrochloride salts by
extraction techniques rarely works as these compounds are
usually unstable in common organic solvents, especially
nucleophilic solvents such as water.15 A number of in situ
generated tert-butyl/tertiary amine combinations were inves-
tigated for use in reaction with 2 (Scheme 8, Table 1). The tert-
with HCl, and poly-THF proved difficult to remove completely.
It was later discovered that faster conversion could be obtained
in higher boiling, minimally nucleophilic solvents, such as
DMAc, NMP, and MeCN at elevated reaction temperatures.
However, a high reaction temperature also accelerated
decomposition of the Burgess-type reagents prepared in this
study. MeCN was chosen as the solvent for sulfamoylation of 2
as it provided a desirable balance between reaction rate and
stability of the Burgess-type reagent.
To further optimize the sulfamoylation reaction using tert-
Bu/DABCO Burgess-type reagent, a robust isolation of the
reagent was preferred for easy handling.16 Due to its reactive
nature, isolation under nonaqueous conditions using a
minimum number of operations was targeted. Addition of
DABCO to Boc sulfonyl chloride (25) resulted in the
coprecipitation of 28 and DABCO·HCl salt, where the ratio
depended on the reaction solvent (Scheme 9). Attempts to
separate 28 from the DABCO·HCl salt by crystallization in
common solvents were unsuccessful.17 The isolation problem
was solved by collecting a 1:1 solid mixture of 28 and DABCO·
HCl salt (28′) from toluene in >98% yield and >98% purity by
quantitative NMR analysis.16b It is worth noting that 28′ has
been prepared on 100−150 kg scale and stored at ambient
temperature for 12 months without a detectable decrease of
potency.
Table 1. Study of in Situ Generated Burgess-Type Reagents
a
in Sulfamoylation
bc
,
entry
amine NR′3/equiv
conversion of 2
ratio of 26/26′/27
1
2
3
4
5
6
7
8
9
DBU/1.0
30%
23%
50%
33%
53%
57%
63%
57%
42%
25/4/1
17/5/1
32/3/16
23/4/6
35/3/15
49/7/1
52/7/3
49/6/2
35/6/1
imidazole/1.2
DTBP/1.5
2,6-lutidine/1.6
DTBP/1.0
sparteine/1.0
DABCO/1.0
sparteine/2.0
DABCO/1.7
Using tert-Bu/DABCO Burgess-type reagent 28′, the current
process for sulfamoylation of diol 2 was established and
successfully carried out in multiple cGMP productions of
pevonedistat (Scheme 10). Although isolable as a solid, Boc
intermediate 26 was difficult to obtain in high purity and was
telescoped into the sequential deprotection step. Diol 2 was
consumed with 2.0 equiv of 28′ in 4−5 h at 50 °C. The excess
amount of 28′ was required to drive 26′ to 27. The end
reaction mixture contained <0.5% 26′ and ∼15% bis-byproduct
27. The removal of the Boc protecting group with strong acid
at this stage would generate a mixture of the desired product 1
and 24. To avoid chromatographic separation of 1 from 24, 27
was first hydrolyzed to olefin 29 under mild acidic conditions,
reported in the original Burgess papers.14 Upon full conversion
of 27, the increase of HCl concentration successfully removed
the Boc groups to afford 1 and 30. Compound 30 was purged
a
Experiments were carried out at 0 °C in THF with 1.0 equiv of
chlorosulfamoyl isocyanate relative to 2, and the reaction mixtures
b
c
were analyzed after 20 h. % a/a. Main impurity was the starting
material 2.
Bu/DABCO and tert-Bu/(−)sparteine combinations demon-
strated the most promising results in terms of reactivity
measured by conversion and of selectivity measured by ratio of
26/26′/27 (Entries 6, 7). An increased amount of base had no
impact on the outcomes (Entries 8, 9). DABCO was selected
for further development due to its low cost and easy removal by
aqueous workup. Although low reaction temperature improved
selectivity, the reaction was limited by the solubility of starting
material 2. THF was chosen as the solvent for the reaction but
was abandoned after the first GMP campaign as a significant
amount of poly-THF was formed during the Boc deprotection
Scheme 9. Synthesis and Isolation of tert-Bu/DABCO Burgess-Type Reagent
E
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Scheme 10. Current Sulfamoylation Process
Scheme 11. Current GMP Pevonedistat Manufacturing Process
completely during aqueous work-up. Charcoal plug filtration
followed by crystallization of the crude product in DCM
afforded free base 1 in >96% (a/a) purity and >50% yield.
Salt Formation. Salt formation from 1 to pevonedistat for
the Discovery route was performed after 1 was purified by
chromatography. To meet GMP API purity and form
specifications without chromatography, a reliable salt formation
procedure that could purge baseline impurities was critical. Free
base 1 was dissolved in EtOH and heated to 50 °C and seeded
with 1% (w/w) pevonedistat. Further slow addition of
ethanolic HCl and cooling gave the final API (pevonedistat)
in high purity (>98% a/a) and the desired form.
EXPERIMENTAL SECTION
■
General. All reagents and solvents were purchased
commercially and used without further purification. NMR
spectra were taken on either a Varian 300 MHz NMR
spectrometer or a Bruker UltraShield 400 MHz NMR. All
HPLC analyses were performed by using an Agilent 1100 series
LC system. Melting points were obtained through DSC using
TA Instruments DSC model Q2000.
HPLC Methods. A. HPLC Purity for 17, 18, and 19 (% a/
a). YMC ODS-AQ, 3 μ, 4.6 × 150 mm, gradient elution with
70:30 0.1% FA in water/0.1% FA in MeCN for 22 min, with
20:80 0.1% FA in water/0.1% FA in MeCN for 3 min, 1.0 mL/
min flow at 35 °C with detection at 208 nm.
B. HPLC Purity for 3 (% a/a). Waters XBridge C18, 3.5 μ, 4.6
× 150 mm, gradient elution with 85:15 0.1% NH4OH in water/
0.1% NH4OH in MeCN for 14 min, with 30:70 0.1% NH4OH
in water/0.1% NH4OH in MeCN for 2 min, 1.0 mL/min flow
at 40 °C with detection at 270 nm.
C. HPLC Purity for 1, 2, and Pevonedistat (% a/a). Thermo
Scientific Aquasil C18, 3 μ, 4.6 × 150 mm, gradient elution with
95:5 0.1% TFA in water/0.1% TFA in MeCN for 37 min, with
10:90 0.1% TFA in water/0.1% TFA in MeCN for 5 min, with
95:5 0.1% TFA in water/0.1% TFA in MeCN for 18 min, 0.500
mL/min flow at 40 °C with detection at 280 nm.
tert-Butyl [(1R,3R,4R,5R)-4-bromo-7-oxo-6-oxabicyclo-
[3.2.0]hept-3-yl]carbamate (18). (1R,4R)-4-[(tert-
Butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylic acid (17,
2.00 kg, 8.80 mol) was dissolved in DME (9.60 L, 92.4 mol)
and DI water (22.4 L, 1240 mol). The solution was stirred for 5
CONCLUSION
■
A manufacturing process was developed for the synthesis of
pevonedistat, a novel and potent NAE inhibitor. The
chromatography free, six-step process was carried out in
multiple 15−30 kg cGMP productions to afford drug substance
with greater than 98% chemical purity (Scheme 11). A high
yielding chiral amino diol 4-HBr synthesis was developed
through bromolactonization of 17, followed by reductive
lactone opening, deprotection and removal of bromide. The
four-step, two isolation process has been demonstrated on a 50
kg scale for multiple cGMP productions. This work also
showcased use of a novel Burgess-type reagent 28′ in the final
selective sulfamoylation step. The increase in yield and removal
of chromatography for this step also contributed to the overall
improvement of the synthesis of pevonedistat.
F
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min. Pyridine (1.78 L, 22.0 mol, 2.50 equiv) was then added
and the reaction stirred until the solid completely dissolved.
The solution was then cooled to 0 °C, and bromine (0.567 L,
11.0 mol, 1.25 equiv) was added slowly over a period of 2 h
maintaining reaction temperature at <5 °C. Once the reaction
was completely determined by HPLC analysis, the reaction
mixture was cooled to −10 °C. The solid formed was collected
by filtration and washed with cold DI water (4.00 L, 222 mol,
0−5 °C). The solid was then suspended in DI water (20.0 L,
1110 mol, 10 vol) and stirred overnight at room temperature.
The solid was filtered, washed with DI water (4.00 L, 222 mol),
and dried under vacuum at 35 °C. The reaction yielded 18
(1.84 kg, 68.4%, 98.0% a/a) as an off-white solid. HPLC
for 4 h. The solids were isolated by filtration and washed with
DCM (2.80 L, 43.7 mol). The solids were dried under vacuum
at 30 °C. The reaction yielded 4-HBr (0.762 kg, 79.6%) as a
light brown solid. 1H NMR (400 MHz, DMSO) δ 7.88 (s, 2H),
4.57 (d, J = 3.9 Hz, 1H), 4.37 (t, J = 5.2 Hz, 1H), 4.15 (d, J =
3.3 Hz, 1H), 3.66 (qd, J = 7.9, 4.0 Hz, 1H), 3.58−3.45 (m, 1H),
3.43−3.21 (m, 1H), 2.26−2.07 (m, 1H), 2.00 (ddd, J = 13.5,
7.7, 1.4 Hz, 1H), 1.88−1.52 (m, 3H); 13C NMR (100 MHz,
DMSO) δ 70.92, 60.20, 49.05, 45.66, 40.49, 31.32; mp: 136−
142 °C.
(1S,2S,4R)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-
(hydroxymethyl)cyclopentanol (3). To a solution of 4-HBr
(0.650 kg, 3.06 mol) in IPA (13.0 L, 170 mol) was added (4,6-
dichloropyrimidin-5-yl)acetaldehyde (5, 0.644 kg, 3.37 mol)
and triethylamine (0.940 L, 6.74 mol). The reaction was stirred
at 75 °C until completion determined by HPLC analysis. The
reaction mixture was then cooled to 45 °C and concentrated to
four volumes under reduced pressure. DI water (8.12 L, 451
mol) was added, maintaining 45 °C. The solution was
concentrated to 13.5 volumes under reduced pressure. After
seed (0.2 mol %) was added, the reaction mixture was stirred
for 1.5 h resulting in a suspension at 45 °C. DI water (2.00 L,
110 mol) was added to the suspension slowly over 30 min
maintaining temperature at 45 °C, and then the reaction
mixture was cooled to 25 °C over 2 h. The reaction was left to
stir at 25 °C overnight and then cooled to 5 °C for 4 h. The
solids were collected by filtration and washed with DI water
(2.60 L, 144 mol). The solids were dried under vacuum at 35
°C. The reaction yielded 3 (0.636 kg, 77.5%, 99.1% a/a) as a
light brown solid. HPLC retention time of 3 (Method B): 13.1
min; 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.92 (d, J =
3.7 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 5.48 (qd, J = 8.6, 5.4 Hz,
1H), 4.75 (s, 1H), 4.54−4.34 (m, 2H), 3.68 (dd, J = 10.2, 7.6
Hz, 1H), 3.50 (dd, J = 10.2, 6.9 Hz, 1H), 2.64−2.44 (m, 1H),
2.32−2.17 (m, 2H), 2.10 (dt, J = 13.6, 9.7 Hz, 1H), 2.02−1.85
(m, 1H); 13C NMR (100 MHz, DMSO) δ 150.49, 150.22,
149.93, 129.20, 116.93, 98.67, 71.16, 60.59, 53.45, 46.16, 42.09,
33.19; m/z: 268.4 (M + H)+; mp: 144−146 °C.
1
retention time of 18 (Method A): 16.9 min; H NMR (400
MHz, DMSO) δ 7.37 (d, J = 6.4 Hz, 1H), 5.20 (d, J = 4.0 Hz,
1H), 4.83 (d, J = 4.4 Hz, 1H), 4.26−4.14 (m, 1H), 4.01 (tt, J =
27.4, 13.6 Hz, 1H), 2.18−1.89 (m, 2H), 1.40 (s, 9H); 13C
NMR (100 MHz, DMSO) δ 169.73, 154.99, 78.47, 77.68,
54.81, 52.27, 51.87, 28.14, 27.20; mp: 173−175 °C.
(1S,2S,4R)-4-Amino-2-(hydroxymethyl)cyclopentanol Hy-
drobromide (4-HBr). To a solution of 18 (1.60 kg, 5.23
mol) in THF (15.2 L, 187 mol) and DI water (0.800 L, 44.4
mol), was added 2.0 M LiBH4 in THF solution (2.61 L, 5.23
mol, 1.00 equiv) slowly over 2 h while the reaction temperature
was maintained at −5 °C. The reaction mixture was stirred until
complete based on HPLC analysis. A solution of ammonium
chloride (2.10 kg, 39.2 mol) in DI water (12.0 L, 666 mol) was
added slowly, maintaining internal temperature <5 °C. The
reaction mixture was then allowed to warm up to room
temperature and the layers separated. The aqueous layer was
extracted two times with MTBE (7.20 L, 60.5 mol). The
organic layers were combined and washed with a mixture of DI
water (8.00 L, 444 mol) and brine (8.00 L, 126 mol). The
organic layer was then concentrated to 2 volumes, and IPA
(16.0 L, 209 mol) was added. The mixture was concentrated to
3 volumes, and 19 was carried into the next step as a solution in
IPA.
The solution of 19 in IPA from the previous step (1.40 kg,
4.51 mol) and IPA (7.00 L, 91.4 mol) were stirred at 30 °C. An
8.84 M solution of hydrobromic acid in water (0.664 L, 5.87
mol) was added slowly to the reaction mixture maintaining a
temperature of <40 °C. The reaction was then heated to 55 °C
and allowed to stir until complete based on HPLC analysis. The
resulting reaction mixture 20 was then cooled to 25 °C. The
IPA solution of 20 (1.31 kg) was transferred to a pressure
reactor.
To the pressure vessel containing 20 was added 10% Pd/C,
50% water (39.8 g, 18.7 mmol), MeOH (7.00 L, 172 mol), and
DIPEA (2.36 L, 13.5 mol). The reactor was purged with
nitrogen and then hydrogen. The vessel was then pressurized to
2.5 bar with hydrogen and allowed to stir at 25 °C until
complete based on HPLC analysis. The catalyst was removed
by filtration and washed with MeOH (2.80 L, 69.2 mol). The
reaction mixture was then concentrated to 3 volumes under
reduced pressure. IPA (14.0 L, 183 mol) was added to the
mixture and concentrated to 3 volumes under reduced pressure.
IPA (7.00 L, 91.4 mol) was added to the mixture and once
more concentrated to 3 volumes under reduced pressure. The
concentrated solution was warmed to 35 °C, and DCM (14.0
L, 218 mol) was added slowly over 1 h while maintaining
temperature at 35 °C. The mixture was kept stirring at 35 °C
for 2 h, then cooled to room temperature over 1 h and stirred
overnight at 25 °C. The reaction was cooled to 0 °C and stirred
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-
7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)-
cyclopentanol (2). The reaction mixture of 3 (0.500 kg, 1.87
mol), 2-butanol (4.00 L, 43.4 mol), (S)-(+)-1-aminoindane
hydrochloride (6, 0.348 kg, 2.05 mol), and DIPEA (0.781 L,
4.48 mol) was heated to 130 °C and the pressure adjusted to 6
bar with nitrogen. The reaction was stirred at 130 °C until
completion determined by HPLC analysis and then cooled to
25 °C. The reaction mixture was concentrated to 3.5 volumes
at 50 °C under reduced pressure. DI water (7.50 L, 420 mol)
was added to the concentrated mixture slowly maintaining
temperature at 50 °C. The resulting suspension was stirred at
50 °C for 1 h and then cooled to 5 °C. The reaction mixture
was stirred at 5 °C overnight. The solid was isolated by
filtration then washed with a chilled (5 °C) solution of 2-
butanol (0.250 L, 2.70 mol) and water (1.25 L, 68.7 mol).
Drying at 50 °C under vacuum afforded 2 (0.552 kg, 81.1%,
99.0% a/a) as a light brown solid. HPLC retention time of 2
1
(Method C): 21.1 min; H NMR (400 MHz, DMSO) δ 8.19
(s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.35−7.08 (m, 5H), 6.65 (d, J
= 3.5 Hz, 1H), 5.92 (q, J = 8.0 Hz, 1H), 5.35 (qd, J = 8.6, 5.5
Hz, 1H), 4.65 (d, J = 3.7 Hz, 1H), 4.36 (ddd, J = 10.0, 8.5, 4.1
Hz, 2H), 3.64 (ddd, J = 12.0, 7.1, 5.1 Hz, 1H), 3.55−3.40 (m,
1H), 3.01 (ddd, J = 15.6, 8.7, 3.0 Hz, 1H), 2.94−2.79 (m, 1H),
2.60−2.35 (m, 2H), 2.13 (dd, J = 8.5, 2.9 Hz, 2H), 2.08−1.91
G
DOI: 10.1021/acs.oprd.5b00209
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(m, 2H), 1.91−1.77 (m, 1H); 13C NMR (100 MHz, DMSO) δ
155.89, 151.12, 149.02, 144.69, 142.97, 127.29, 126.28, 124.48,
124.11, 121.53, 102.77, 98.79, 71.28, 60.72, 54.49, 52.24, 46.21,
42.37, 33.48, 33.27, 29.72; m/z: 365.2 (M + H)+; mp: 141−143
°C.
portion of 1.25 M HCl in EtOH (13.9 mL, 0.017 mol) was
added over 1 h resulting in a suspension. The mixture was
stirred at 55 °C for 2 h and then cooled to 25 °C over 2 h. The
reaction was stirred at 25 °C overnight. The solids were
collected by filtration, washed with EtOH (28.0 mL, 0.480
mol), and dried under vacuum at 35 °C to afford pevonedistat
(14.0 g, 92.5%, 99.0% a/a) as a white solid. HPLC retention
((1S,2S,4R)-4-(4-(((S)-2,3-Dihydro-1H-inden-1-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)-
methyl Sulfamate (1). The reaction mixture of 2 (0.400 kg,
1.10 mol), (1,4-diazabicyclo[2.2.2]octan-1-ium-1-ylsulfonyl)
(tert-butoxycarbonyl)amide·1,4-diazabicyclo[2.2.2]octane (1:1)
hydrochloride (28′, 0.966 kg, 2.20 mol), and MeCN (3.20 L,
61.5 mol, 8 vol) was heated to 53 °C. The resulting suspension
was stirred for 5 h and then cooled to 15 °C. To the reaction
mixture was added 0.6 M HCl in water (2.3 L) slowly to
maintain temperature at 15 °C. The biphasic reaction mixture
was stirred at 15 °C until the bis-sulfamoylated impurity (27)
was <0.5% (a/a) determined by HPLC analysis. Sodium
chloride (0.185 g, 3.17 mol) was added to the reaction mixture
to promote complete phase separation. The aqueous layer was
removed, and the organic layer was cooled to 5 °C. To the
MeCN solution was slowly added aqueous 12 M HCl (1.28 L,
15.36 mol) while the reaction temperature was kept at 5 °C.
The reaction mixture was then warmed to 20 °C and allowed to
stir until the deprotection was complete determined by HPLC
analysis. An aqueous solution of 2.12 M NaHCO3 (4.80 L, 10.2
mol) was added to the reaction mixture to achieve pH > 7. The
aqueous layer was removed and EtOAc (3.20, 32.8 mol, 8 vol)
added to the organic layer. The organics were washed with
water (2.00 L, 111 mol) four times, then passed through a
charcoal plug (20 wt %). The charcoal plug was washed with
EtOAc (0.100 L), and the wash was combined with treated
reaction mixture. The organic solution was concentrated to 2
volumes and then warmed to 35 °C. DCM (8.00 L, 125 mol)
was added slowly while the internal temperature was kept at 35
°C. The solution was seeded with 1 (0.1 wt %) and held for 30
min. DCM (4.00 L, 62.4 mol) was added slowly at 35 °C and
then stirred for 1 h. The suspension was cooled to 25 °C over 2
h and left overnight. The resulting suspension was cooled to 5
°C and was stirred for 1 h. The solids were collected by
filtration, washed with DCM (1.20 L, 18.7 mol), and dried at 30
°C under vacuum. The reaction yielded 1 (0.285 kg, 58.5%,
93.0% a/a) as an off-white solid. HPLC retention time of 1
1
time of pevonedistat (Method C): 22.6 min; H NMR (400
MHz, DMSO) δ 9.70 (s, 1H), 8.39 (s, 1H), 7.63 (s, 1H), 7.45
(s, 2H), 7.41−7.20 (m, 4H), 7.04 (s, 1H), 5.78 (s, 1H), 5.44 (s,
1H), 4.42−4.28 (m, 1H), 4.24 (dd, J = 9.7, 6.9 Hz, 1H), 4.05
(dd, J = 9.6, 8.0 Hz, 1H), 3.18−2.99 (m, 1H), 2.91 (dt, J = 15.6,
7.7 Hz, 1H), 2.81−2.57 (m, 2H), 2.24−1.86 (m, 6H). 13C
NMR (100 MHz, DMSO) δ 149.12, 145.71, 143.23, 142.11,
141.30, 128.28, 126.64, 124.97, 124.82, 124.49, 102.57, 101.74,
70.67, 69.22, 57.38, 53.14, 42.52, 42.40, 33.57, 32.56, 29.80; m/
z: 444.4 (M + H)+; mp: 155−157 °C.
AUTHOR INFORMATION
Corresponding Author
*Tel.: 617-551-2966; fax: 617-444-1480; e-mail: lei.zhu@
takeda.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the entire NAE team for helpful discussions.
Special thanks are given to Dr. Qing Lu for assistance in
structure identification and Ms. Beth Piro for analysis support.
REFERENCES
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(Method C): 22.6 min; H NMR (400 MHz, DMSO) δ 8.19
(s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.45 (s, 2H), 7.31−7.26 (m,
2H), 7.22 (t, J = 6.6 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 6.66 (d, J
= 3.5 Hz, 1H), 5.92 (q, J = 8.0 Hz, 1H), 5.39 (qd, J = 8.8, 5.7
Hz, 1H), 4.95 (d, J = 3.9 Hz, 1H), 4.42−4.31 (m, 1H), 4.25
(dd, J = 9.7, 7.0 Hz, 1H), 4.07 (dd, J = 9.6, 8.0 Hz, 1H), 3.01
(ddd, J = 15.7, 8.7, 3.0 Hz, 1H), 2.95−2.81 (m, 1H), 2.81−2.65
(m, 1H), 2.58−2.49 (m, 1H), 2.31−1.86 (m, 5H); 13C NMR
(100 MHz, DMSO) δ 155.91, 151.18, 149.02, 144.66, 142.98,
127.30, 126.28, 124.49, 124.11, 121.68, 102.83, 98.86, 70.82,
69.37, 54.48, 52.15, 42.58, 42.25, 33.50, 33.26, 29.72; m/z:
444.4 (M + H)+; mp: 164−166 °C.
((1S,2S,4R)-4-(4-(((S)-2,3-Dihydro-1H-inden-1-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)-
methyl Sulfamate·Hydrochloride (Pevonedistat). The reac-
tion mixture of 1 (14.0 g, 0.032 mol) in absolute EtOH (0.140
L, 2.40 mol) was warmed to 70−75 °C resulting in a solution.
The reaction mixture was cooled to 55 °C, and 1.25 M HCl in
EtOH (13.9 mL, 0.017 mol) was added over 30 min. The
solution was then seeded with pevonedistat (0.1 wt %) and
stirred for 10 min to ensure seeds did not dissolve. A second
H
DOI: 10.1021/acs.oprd.5b00209
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Org. Process Res. Dev. XXXX, XXX, XXX−XXX