Use of a "catalytic" Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch

Article abstract of DOI:10.1002/anie.201509922

A general, efficient method for C-N cross-coupling has been developed using N,N-dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. Additionally, the method was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches. Going with the flow: A general flow method developed for C-N cross-coupling using N,N-dimethyloctanamide as a catalytic cosolvent was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. It was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches.

Full text of DOI:10.1002/anie.201509922

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International Edition: DOI: 10.1002/anie.201509922
German Edition: DOI: 10.1002/ange.201509922
Cross-Coupling
Use of a “Catalytic” Cosolvent, N,N-Dimethyl Octanamide, Allows the
Flow Synthesis of Imatinib with no Solvent Switch
Jeffrey C. Yang, Dawen Niu, Bram P. Karsten, Fabio Lima, and Stephen L. Buchwald*
try.[16] Amphiphilic solvents facilitate contact between
organic- and water-soluble components of a reaction while
maintaining a high local concentration of the organic
reactants, thereby accelerating mass-transfer and overall
reaction rates. In addition to these benefits, amphiphilic
solvents are capable of solubilizing a wide range of com-
pounds, and may mitigate crystallization and minimize the
need for switching solvents in a multistage continuous-flow
process. As a result, we believed that the use of organic
amphiphiles in biphasic solvent systems might permit
À
Abstract: A general, efficient method for C N cross-coupling
has been developed using N,N-dimethyloctanamide as a cata-
lytic cosolvent for biphasic continuous-flow applications. The
described method was used to generate a variety of biaryl-
amines and was integrated into a two-step sequence which
converted phenols into biarylamines via either triflates or
tosylates. Additionally, the method was applied to a three-step
synthesis of imatinib, the API of Gleevec, in good yield without
the need of solvent switches.
À
T
he use of continuous-flow technology in synthesis has
a broader range of C N cross-coupling reactions to be
performed under continuous-flow conditions.
received an increasing amount of attention over the past
decade in both academia and industry.[1] Compared to tradi-
tional batch methods, continuous-flow offers many benefits,
including safer manipulation of reactions at high pressure and
temperature, the ability to scale chemical reactions in a more
straightforward manner, and the in situ generation and
consumption of intermediates, thus combining multiple
synthetic steps into a single process.[1,2]
Herein we report the identification and use of N,N-
dimethyloctanamide (DMO, 1; Figure 1) as an amphiphilic
The importance of aromatic amines and their derivatives
is demonstrated by their prevalence in pharmaceutical agents
À
and organic materials. Palladium-catalyzed C N cross-cou-
Figure 1. Properties of N,N-dimethyloctanamide.
pling[3] has become a widely applied method for the prepa-
ration of these compounds. As a continuation of our interest
À
in developing practical methods for C N bond construction,
organic cosolvent which enabled the synthesis of a wide range
À
we initiated a program for the development of general
methods to perform palladium-catalyzed amination in con-
tinuous-flow reactors.[4] Previous studies by us and other
research groups have revealed several difficulties with
of (hetero)arylamines by a palladium-catalyzed C N cross-
coupling reaction under continuous-flow conditions. Further-
more, we demonstrate that this method can be integrated into
a two-step sequence for the direct conversion of phenols into
amines, as well as a three-step synthesis of imatinib, the active
pharmaceutical ingredient of the anticancer agent Gleevec,
under continuous-flow conditions. Notably, these multistep
reaction syntheses were performed without in-line purifica-
tion of any intermediates or solvent exchanges between steps.
We have previously reported a system wherein biphasic
À
transitioning C N cross-coupling to continuous-flow condi-
tions.[5] The formation and precipitation of crystalline prod-
ucts and inorganic salts during cross-coupling reactions often
result in clogging of the continuous-flow reactor. Moreover,
downstream solvent switches are often required because of
the limited range of solvents suitable for cross-coupling. The
formation of byproducts may also impact downstream
reactions, thus complicating multistep sequences in a contin-
uous-flow reactor. As a consequence, multistep continuous-
À
conditions were utilized for C N cross-coupling. However,
even though phase-transfer catalyst additives were able to
greatly increase the efficiency of the reaction, the generality
of such a system was still severely impaired by the solubility of
reagents and products in toluene, particularly heteroaromatic
compounds. We envisioned that DMO would be a practical
solution for continuous-flow chemistry because it has similar
Hansen solubility parameters to those of dichloromethane,[6b]
low solubility in water (4.3 gLÀ1),[6c] a reported toxicological
profile comparable to common laboratory solvents,[6c,d] is
readily availabile as a high production volume chemical,[6c]
and was previously used as a crystallization inhibitor and for
crop protection formulations.[6,7] We therefore evaluated its
use in the cross-coupling of aniline (2) and 4-chloroanisole (3)
in the presence of the XPhos-based[8] precatalyst 7 under
À
flow processes which utilize a C N cross-coupling step remain
rare.
A large body of work has demonstrated the advantages of
amphiphilic organic solvents and additives in batch chemis-
[*] J. C. Yang, D. Niu, B. P. Karsten, F. Lima, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18–490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509922.
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biphasic conditions with aqueous KOH as the base. When the
reaction was performed in a perfluoroalkoxyalkane (PFA)
tube reactor with neat DMO as the solvent, low conversion
was observed, presumably because of inefficient mixing of the
two phases (Table 1, entry 1). The use of a stainless steel
Using the above-described reaction conditions, we
explored the generality and applicability of the protocol
(Table 2). A wide variety of aryl bromides and chlorides,
bearing either electron-donating or electron-withdrawing
substituents, were efficiently coupled with aniline partners
À
À
Table 1: Optimization of the palladium-catalyzed C N cross-coupling
Table 2: Substrate scope of C N cross-coupling reaction between
reaction under continuous-flow conditions.[a]
arylamines and aryl (pseudo)halides.[a]
Entry
Solvent
Pd*
Y [%] (C [%])
tR [min]
1[b]
2
3
4
5
6
7
8
9
1
1
1
7
7
8
8
8
8
8
8
8
7 (11)
68 (74)
15
15
15
7.5
7.5
7.5
7.5
7.5
7.5
97 (>95)
98 (>95)
95 (>95)
93 (>95)
70 (71)[c]
80 (84)
toluene/1=1:1
toluene/1=9:1
2-MeTHF/1=9:1
toluene
2-MeTHF
9
93 (94)[c]
[a] Conversions and yields were determined by GC analysis of the crude
reaction mixture. See the Supporting Information for details. [b] 0.04’’
PFA tubing was used as the reaction vessel. [c] Prolonged reaction times
gave full conversion and clogging of the reaction vessel because of low
product solubility. Ms=methanesulfonyl.
[a] Yields of isolated products are reported (average of 2 runs,
approximately 1–4 mmol collected). See the Supporting Information for
details.
packed-bed reactor apparatus,[4a] a device previously de-
scribed for achieving efficient mixing in a biphasic flow
system, improved the yield significantly (entry 2). Full con-
version and excellent yield were obtained when the Brett-
Phos-based[9] precatalyst 8 was used instead of 7 (entry 3).
Further optimization revealed that toluene/DMO mixtures
containing as little as 10% DMO gave similar results to those
obtained using DMO as a neat solvent (entries 4 and 5). In
addition, we found that 2-methyltetrahydrofuran (2-
MeTHF), a solvent derived from renewable sources and
suitable for large-scale production,[10] also gave comparable
results when 10% DMO was utilized as an additive (entry 6).
Control experiments showed that the use of either toluene or
2-MeTHF in the absence of DMO resulted in incomplete
conversion within the designated reaction times. Upon
extended reaction times to achieve full conversion in toluene
(entry 7), the reaction vessel clogged because of the poor
solubility of the product. Although the use of the amphiphilic
solvent 9 also gave high conversion of the starting material
and yield of the product 4, clogging of the reactor occurred
after prolonged reaction times. Therefore, the reaction
conditions outlines in either entry 5 or 6 of Table1 were
selected for most of the following studies.
(10a,b, and 10g,h). Ortho substitution in either the aryl halide
or arylamine was accommodated (10c–e). In addition, aryl
triflates (10 f) were excellent substrates under these reaction
conditions, with minimal hydrolysis observed. Besides aryl
amines, primary alkyl amines could also be successfully
converted into product (10g). As a consequence of the precise
control of the reaction times under continuous flow con-
ditions, even readily hydrolyzed methyl esters, provided high
yield of desired product (10b–e, and 10h). To demonstrate the
potential applicability of this method, fenofibrate, a medicine
used to reduce cholesterol levels, was subjected to the
reaction conditions and coupled with 3-trifluoromethylaniline
to give 10h in excellent yield.
Next, we turned our attention to expanding the scope of
this method to include heteroaromatic compounds. The
results are summarized in Table 3. A variety of heterocycles,
including pyridines (11a–c), thiophene (11d), benzothiazole
(11e), quinoline (11 f), piperazine (11g), and phenothiazine
(11h), were efficiently coupled with aromatic, heteroaro-
matic, or aliphatic amine partners. Notably, chlorpromazine,
an anti-psychotic drug, was coupled with 2-aminopyridine
under our reaction conditions to give 11h in excellent yield.
Substrates containing base-sensitive functional groups, such
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À
Table 3: Substrate scope of C N cross-coupling reaction between
of phenols into arylamines without isolating the triflate
heteroarylamines and heteroaryl (pseudo)halides.[a]
intermediate would be of considerable interest. We have
previously reported a similar sequence in flow, and the
complete removal of methylene chloride from the first step by
microfluidic distillation and solvent exchange to dimethylfor-
mamide was required for a subsequent Heck coupling.[2f]
After experimentation, we found that the transformation of
phenols into secondary amines, without the isolation of the
triflate intermediate, could be accomplished in a flow system
as shown in Scheme 1. While the triflation of a phenol is often
carried out at low temperature and with the slow addition of
triflic anhydride in a batch reactor, this transformation could
be performed at room temperature in minutes using aqueous
K3PO4 as the base in a continuous-flow reactor. The reaction
mixture from the first step was directly introduced into
another packed-bed reactor with an aryl amine substrate, the
palladium precatalyst 8, and additional K3PO4 to give the
desired biarylamine product in excellent yields over two steps
(12a,b). In contrast to previous reports of the use of in situ
generated aryl triflates in continuous flow, neither in-line
purification nor solvent switching was required in this process.
À
In addition, we found that a phenol tosylation/C N cross-
coupling sequence could also be similarly accomplished
(12c).[12]
À
To further demonstrate the utility of this C N cross-
coupling technology, we applied it in a flow-based synthesis of
imatinib (19; Scheme 3), a tyrosine kinase inhibitor widely
used in the treatment of chronic myeloid leukemia.[13] In an
elegant demonstration of the power of flow methodology in
the preparation of important pharmaceutical substances, Ley
and co-workers[2g,h] described the flow synthesis of imatinib, as
depicted in Scheme 2. Based on this synthetic sequence, Ley
[a] Yields of isolated products are reported (average of 2 runs,
approximately 1–4 mmol collected). See the Supporting Information for
details.
as ketones (11d) and esters (11g), were again well tolerated
under these continuous-flow conditions.
In light of the broad scope demonstrated by our reaction
conditions, we next explored the potential of integrating this
À
C N cross-coupling reaction into multistep sequences in flow.
In this context, we were interested in converting phenols into
biarylamines via aryl triflate intermediates (Scheme 1). Aryl
triflates are recognized as highly reactive coupling partners in
[3f]
À
C N cross-coupling reactions. However, the lack of com-
mercially available triflates and their instability necessitate
their preparation prior to their use, significantly hampering
their application. We reasoned that the two-step conversion
Scheme 2. Three-step flow synthesis of imatinib.
and co-workers reported a flow synthesis of imatinib featuring
the sophisticated use of an in-line solvent switching apparatus,
solid supported reagents, and purification cartridges to
provide imatinib with minimal manual handling of inter-
mediates. The final product was purified by chromatography
to provide pure imatinib in 32% overall yield.
We have also reported the synthesis of imatinib using
batch protocols.[15] By using our new C N cross-coupling
technology, a more streamlined continuous-flow process for
the synthesis of imatinib is depicted in Scheme 3. The first
step, coupling of 3-bromo-4-methylaniline (13) with 4-chloro-
À
Scheme 1. Two-step flow conversion of phenols into biarylamines via
either aryl triflates or tosylates. Yields of the isolated products are
reported (average of 2 runs, approximately 1–4 mmol collected). See
the Supporting Information for details. Tf =trifluoromethanesulfonyl.
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manipulation of reaction intermediates or solvent exchange,
uses lower catalyst loading, and produces the target product in
higher overall yield. We expect this strategy of using DMO as
a cosolvent in biphasic systems to be applicable to other
multistep flow sequences, especially those involving cross-
coupling reactions.
Acknowledgements
We thank Novartis International AG for funding. We thank
Drs. Berthold Schenkel, Benjamin Martin, and Gerhard Penn
for insightful suggestions. We thank Dr. Michael Pirnot, Dr.
Yiming Wang, and Dr. Christine Nguyen for assistance with
the preparation of this manuscript.
Scheme 3. Flow synthesis for imatinib. Boc=tert-butoxycarbonyl.
methyl-benzoyl chloride (14) to form the amide 15, was
performed in a 2-MeTHF/H2O biphasic system with KOH as
the base (Schotten–Baumann conditions[14]). Complete con-
version was achieved within three minutes at room temper-
ature and 15 was isolated in 87% yield. The next reaction
step, the nucleophilic substitution of the benzylic chloride 15
with 1-methylpiperazine (16), was implemented by directly
using the output of the first reactor. An aqueous solution of 16
was injected into the system and the mixture was pumped
through a packed-bed reactor at 1208C. The residence time in
the second reactor was 15 minutes and the reaction yield over
the first two steps was 84% as determined by 1HNMR
analysis of the crude reaction mixture. The last step in the
Keywords: biaryls · cross-coupling · flow chemistry · palladium ·
synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2531–2535
Angew. Chem. 2016, 128, 2577–2581
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À
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whole synthesis.
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À
a flow-based C N cross-coupling reaction featuring the use of
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À
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À
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À
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Received: October 23, 2015
Revised: December 4, 2015
Published online: January 12, 2016
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