Modular Continuous Flow Synthesis of Imatinib and Analogues

Article abstract of DOI:10.1021/acs.orglett.9b02259

A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C-N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixtures.

Full text of DOI:10.1021/acs.orglett.9b02259

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Modular Continuous Flow Synthesis of Imatinib and Analogues
Wai Chung Fu and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
S
* Supporting Information
ABSTRACT: A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib
analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C−N coupling
sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to
excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed
apparatuses due to the judicious manipulation of flow setups and solvent mixtures.
he Bcr-Abl tyrosine kinase inhibitor imatinib is the active
T
pharmaceutical ingredient (API) of Gleevec.1 It is
currently listed on the World Health Organization’s List of
Essential Medicines as a treatment for chronic myelogenous
leukemia (CML) and gastrointestinal stromal tumor (GIST).2
The batch production process of this API is labor-intensive and
time-consuming and involves multistep reaction sequences and
purifications.3 Recently, continuous flow technology has
emerged as an efficient tool in API synthesis owing to its
power in telescoping multiple synthetic steps into a stream-
lined system and circumventing laborious purification
processes of intermediates.4 The many characteristic benefits
of flow chemistry5 have prompted our laboratory to develop
continuous flow platforms for greater access to various APIs.6
A large body of work has summarized imatinib-resistant
mutations in the Bcr-Abl kinase domain.7 One of the major
constraints associated with current imatinib syntheses, either in
batch or flow, is the limited availability and variation in
substitution patterns of functionalized substrates which render
a narrow derivatization scope for high throughput discovery of
new tyrosine kinase inhibitors.3,8 While following literature
precedents, we also identified a multitude of challenges for the
continuous production of imatinib. In 2010, the Ley group
utilized a strategic disconnection that enabled the synthesis of
imatinib in flow with minimal intervention (Figure 1a).9
However, solvent-switching apparatuses and scavenger col-
umns were required for in-line workup and purification due to
solvent and reagent incompatibilities between individual
reaction steps.8,9 The use of solid-supported reagents and
purification cartridges can offset the continuity of a flow system
because of the eventual replacement of consumable materials.
The formation of inorganic solids and thus clogging of
microreactors has also been a long-standing problem in the
deployment of transition-metal-mediated C−N bond forming
steps. Although these concerns have been addressed by means
Figure 1. Continuous flow synthesis of imatinib and analogues.
of acoustic irradiation10 or packed-bed mixing under biphasic
conditions,11 prolonged continuous operation of Pd-catalyzed
reactions in packed-bed reactors may result in the aggregation
of palladium black precipitate within the packing materials or
filtering frits, wherein undesirable side reactions or clogging
problems might arise.
Received: July 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02259
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Letter
Herein we devised a new modular assembly of imatinib and
structural analogues in a single uninterrupted reaction stream
(Figure 1b). A Pd-catalyzed chemoselective amidation/
amination process directly employing anilines and amides
avoids cumbersome reaction steps to reveal −NH2 from nitro
or protecting groups.3a From a standpoint of versatility and
practicality, aryl halides and nitriles are generally cost-effective
and more accessible than their corresponding anilines or acid
chlorides12 and are often more stable toward light, heat, and
moisture.13 Furthermore, a catalytic flow hydration of nitriles
was developed to give amides with minimal byproduct
formation, posing less uncertainty in downstream processes.
Our investigations commenced with the proposed chemo-
selective amidation using a model reaction between benzamide
and 2,4-dihalotoluene under batch conditions. The optimiza-
tion process has been detailed in the Supporting Information
(Tables S1 and S2). Although low chemoselectivity and
product yields were observed when dichloro- or dibromoto-
luene was used, favorable results were obtained using 4-bromo-
2-chlorotoluene. Buchwald’s precatalyst BrettPhos Pd G4
proved to be the best catalyst while its improved solubility in
organic solvents was deemed beneficial for utilization in a flow
process.14 A biphasic mixture of K3PO4(aq)/1,4-dioxane was
optimal for the reaction as the base and solvent, and also
ensured the solubility of the inorganic salts in flow. Complete
chemoselectivity with an 80% yield of 1 was obtained under
the optimized batch reaction conditions (eq 1).
may significantly increase the interfacial contact. In practice,
compound 3a (Scheme 1) was obtained in 69% yield within a
Scheme 1. Substrate Scope of Chemoselective Amidation in
a
Continuous Flow
a
Isolated yields are reported. See Supporting Information for details.
residence time (tR) of 15 min at 120 °C in a stainless-steel coil
reactor (0.04” inner diameter). Utilization of a 200 psi back
pressure regulator (BPR) allowed for the superheating of water
and dioxane at 150 °C without solvent vaporization and
increased the isolated yield of 3a to 83%. Notably, replacing
the coil reactor with a sand packed-bed reactor resulted in
clogging due to aggregation of palladium black on the frit of
the reactor output.
Next, we explored the generality of our chemoselective
amidation module (Scheme 1). Both electron-rich and
-deficient aryl dihalides (3a−3g) were amidated to give the
desired products in good yields and complete chemoselectivity.
Importantly, sterically unhindered bromoaryl chlorides (3b,
3d, 3h−3l) reacted smoothly and afforded chloroaryl amides
in moderate to good yields. Heteroatoms incorporated in the
aryl dihalides (3j) or amides (3m) were tolerated. The scope
of our flow reaction could be further expanded to lactams
(3n−3o) and anilines (3p−3q). For polar amides with a low
solubility in dioxane (3m, 3o), 2−15% (v/v) of methanol was
employed as a cosolvent.
Next, we set out to translate the batch process to flow. It was
found that when three separate streams of catalyst, substrates,
and base were mixed in a cross mixer with a small inner
diameter (0.02” id), a near-homogeneous mixture resulted as
shown in Figure 2a. We reasoned that minimized aqueous
microdroplets were produced from the vigorous mixing
between dioxane and the alkaline solution which is different
from a typical segmented flow afforded from a 2-MeTHF/
water mixture (Figure 2b).11b Although packed-bed mixing was
previously shown to be critical for biphasic C−N couplings in
flow,11 we postulated that generation of aqueous microdroplets
Having established the C−N coupling key to our synthetic
sequence, we next developed a continuous flow hydration of
nitriles for the preparation of amides. In 2014, Ley and co-
workers developed a continuous flow hydration by passing the
nitriles through a manganese dioxide packed-bed reactor.15
However, the nitrile precursor to 4a and thus imatinib
(Scheme 2) was found to be not compatible with MnO2 and
the flow reaction only gave a trace amount of formylbenzoni-
Figure 2. An illustrated comparison of (a) segmented and (b) near-
homogeneous flow.
B
DOI: 10.1021/acs.orglett.9b02259
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Scheme 2. Substrate Scope for Continuous Flow Hydration
of Nitriles
Scheme 3. Biphasic Continuous Flow C−N Cross-Coupling
Using a Coil Reactor
a
mixture. The Y-mixer offered milder laminar mixing,
preventing the precipitation and thus aggregation of 5 upon
forming the free base with K3PO4. The C−N coupling
furnished a 97% isolated yield of 6 with a tR of 15 min in a
stainless-steel coil reactor. Prior to this work, this biphasic
coupling reaction was only successful in a packed-bed
reactor.11
We next sought to telescope the three optimized modules to
establish a three-step streamlined flow synthesis of imatinib.
The outlet of the hydration module was directly used without
any purification or workup steps (Scheme 4). The aryl halide
a
Isolated yields are reported. See Supporting Information for details.
b
20 mol % of Cs2CO3 was used.
Scheme 4. Telescoped Synthesis of Intermediate 7
trile as a result of oxidative cleavage. Recently, the hydration of
nitriles was found to proceed in the presence of a
stoichiometric amount of K2CO3 using conventional heating
in 3 h.16 We anticipated that heating the reaction mixture
above its atmospheric boiling point under continuous flow
conditions would allow for a significantly increased reaction
rate.5b,c Indeed, stoichiometric quantities of K2CO3 promoted
the hydration in a stainless steel coil reactor at 150 °C and
yielded 75% of 4a after a tR of 5 min (Table S3). Reaction
optimization led to complete conversion employing 10 mol %
Cs2CO3 and a 240 psi BPR within 15 min at 180 °C. In
practice, a solution of the nitrile in 1,4-dioxane/DI water (0.8
M, 2:3 v/v) was passed through a coil reactor to give 4a in 91%
isolated yield (Scheme 2). Importantly, this catalytic hydration
process generates minimal wastes and shares the same solvent
mixture with the C−N coupling reactions to eliminate the
need for either in-line solvent switches or purification between
individual steps. Other nitrile precursors applicable to imatinib
analogues similarly underwent hydrolysis smoothly to afford
the corresponding amides in 75−95% isolated yield (4a−4g).
Chloro- (4h), amino- (4j), and heterocycles (4k, 4l, 4m) were
well tolerated under the continuous flow conditions. Alkenyl
(4n) and aliphatic (4o) nitriles were also applicable substrates.
Organic cosolvents such as i-PrOH and t-BuOH could be used
without affecting the reaction in cases where the starting
materials possessed low solubility in water and 1,4-dioxane.
The last module in our synthetic sequence constituted the
C−N bond formation of 2-aminopyrimine 5 and a sterically
hindered aryl chloride (Scheme 3). Notably, the low solubility
of 5 in organic solvents proved challenging. Hence, 5 was
dissolved in water as its conjugate acid for injection into the
system to form a homogeneous solution after mixing with the
Pd catalyst in a T-mixer. This homogeneous solution was then
combined with the flow slugs afforded from the streams of
K3PO4 and 2-chlorotoluene to give a near-homogeneous
and Pd precatalyst were first mixed and subsequently
combined with separate streams of K3PO4 and the newly
generated amide intermediate in a cross-mixer (0.02” id) to
form a mixture as shown in Figure 2a. Here, 0.306 M was
found to be an optimal concentration for the Pd-catalyzed flow
amidation with a stoichiometry of the amide and aryl halide of
1.3:1. Decreasing the global concentration of the system by
half led to significant losses in overall product yield while
increasing the concentration ultimately led to clogging in the
cross-mixer due to crystallization of polar amide intermediates.
A stream of i-PrOH was introduced after the reactors to
prevent precipitation of polar compounds and clogging of the
BPR. Within 33 min, intermediate 7 was delivered in 67%
isolated yield over two reaction steps.
Finally, the remaining C−N cross-coupling of 7 and 2-
aminopyrimidine 5 was integrated into the hydration/
amidation sequence (Scheme 5). However, the poor solubility
of 5 in the reaction mixture again presented a significant
challenge. Neutralization of 5·HCl with a basic aqueous
solution caused crystal aggregation in the mixing unit. Thus,
K3PO4, Pd precatalyst, and the reaction mixture from the first
C
DOI: 10.1021/acs.orglett.9b02259
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a
Scheme 5. Continuous Flow Synthesis of Imatinib and Analogues
a
See the Supporting Information for detailed reaction conditions.
two telescoped steps were first mixed before joining the stream
of 5·HCl to enable faster flow rates and an overall more dilute
stream. Additionally, the global concentration of the system
was decreased by 25% and 5·HCl was dissolved in a 1:1
dioxane/DI water mixture to increase the content of organic
solvent. Despite these approaches to avoid immediate
precipitation, clogging of the Y-mixer before the final reactor
still occurred shortly after equilibration of the flow system. The
gradual solid aggregation of 5 in the Y-mixer was perceived as a
result of seeded crystallization triggered by solvent incom-
patibilities during system equilibration. To address this, the
streams of i-PrOH and the hydration module were first
pumped into the system for a period of 30 min to equilibrate
the telescoped system with i-PrOH. The remaining modules
were started afterward, as the excess i-PrOH could dissolve and
carry away the unreacted materials. As described above, the
reaction mixtures afforded by the mixing units constituted a
semihomogeneity, and the final amination reaction could be
performed in a stainless-steel coil reactor. Imatinib (8a) was
isolated in 58% overall yield with a total tR of 48 min and a
production rate of 0.663 mmol h−1.
and amidation modules both exhibited a broad scope with
good to excellent yields. To the best of our knowledge, our
system delivers the highest production rate of imatinib while
packed-bed apparatuses, in-line purifications, and solvent
exchanges between individual steps were not required. We
have shown that inadequate mass transfer of biphasic C−N
cross-coupling reactions under continuous flow conditions can
be addressed by meticulous manipulation of the flow setup and
solvent mixtures. Taken together, these results would be useful
for the future design and implementation of continuous flow
sequences employing biphasic reactions using simple compo-
nents.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02259.
Experimental procedures, characterization data and
spectra of new compounds (PDF)
To demonstrate the utility of our method, the three
individual substrates were varied and two novel imatinib
analogues were rapidly generated in 57−66% yield with
complete chemoselectivity (8b−8c) (Scheme 5). Notably,
analogue 8d was prepared by performing two C−N cross-
coupling reactions on a meta-dichloroarene intermediate in the
final step, demonstrating the ability of our system to access
commercially unavailable structures in situ. We anticipate that
the tunability of substitution patterns and structures of both
aryl nitriles and halides could provide a higher structural
diversity for drug discovery in comparison with the existing
methods.3
In conclusion, a continuous flow platform for the rapid and
modular synthesis of imatinib and analogues has been
developed. Our three-step synthetic sequence uses widely
available nitriles and aryl halides to assemble imatinib and
related analogues via sequential hydration and chemoselective
C−N cross-couplings. The newly developed catalytic hydration
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tfj@mit.edu.
ORCID
Wai Chung Fu: 0000-0002-7181-0057
Timothy F. Jamison: 0000-0002-8601-7799
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Long V. Nguyen (MIT) and Dr. Rachel L.
Beingessner (MIT) for helpful discussions. W.C.F. thanks The
Croucher Foundation for a postdoctoral fellowship. This work
was supported by the DARPA Make-It program under
Contract Number ARO W911NF-16-2-0023.
D
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Letter
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