Continuous Flow Synthesis of ACE Inhibitors From N-Substituted l-Alanine Derivatives

Article abstract of DOI:10.1002/chem.201904400

A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h^?1, all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h^?1.

Full text of DOI:10.1002/chem.201904400

DOI: 10.1002/chem.201904400
Communication
&
Kinetics
Continuous Flow Synthesis of ACE Inhibitors From N-Substituted
l-Alanine Derivatives
Christopher P. Breen and Timothy F. Jamison*[a]
step to afford perindopril 6. Warner-Lambert’s approach in-
Abstract: A strategy for the continuous flow synthesis of
stead relied on the activation of 18 with highly toxic phosgene
angiotensin converting enzyme (ACE) inhibitors is de-
to produce N-carboxyanhydride 19.[5] Again, the activated in-
scribed. An optimization effort guided by in situ IR analy-
termediate was isolated before amide coupling with 20.
sis resulted in a general amide coupling approach facilitat-
As an alternative to these batch syntheses, we envisioned a
ed by N-carboxyanhydride (NCA) activation that was fur-
continuous flow approach that would unite these structurally
ther characterized by reaction kinetics analysis in batch.
related products under a single synthetic paradigm while also
The three-step continuous process was demonstrated by
mitigating process intensity. Specifically, we aimed to develop
synthesizing 8 different ACE inhibitors in up to 88% yield
a rapid, scalable, and safe synthesis of ACE inhibitors starting
with throughputs in the range of ꢀ0.5 ghÀ1, all while
from well-established N-substituted l-alanine derivatives 14
avoiding both isolation of reactive intermediates and pro-
and 20 as a part of our ongoing interest in this class of APIs.[6]
cess intensive reaction conditions. The process was further
Mild activation with N,N-carbonyldiimidazole (CDI) would pro-
developed by preparing enalapril, a World Health Organi-
duce competent NCA amide coupling partners (Figure 1C) and
zation (WHO) essential medicine, in an industrially relevant
subsequent coupling with various tBu-protected amino acid
flow platform that scaled throughput to ꢀ1 ghÀ1.
derivatives would be followed by acidic deprotection to reveal
the API.
Continuous flow tactics for amide coupling have emerged
as a preferable alternative to traditional batch approaches.[7]
ACE inhibitors are a safe and effective treatment for hyperten-
sion.[1] Despite the structural similarities shared between these
Notable advantages of these works include precisely controlled
active pharmaceutical ingredients (APIs) (Figure 1A), a number
of different synthetic approaches have been pursued.[2] Herein,
we report a synthetic plan that consolidates the preparation of
these essential medicines to a single three-step continuous
process.
activation and amination conditions wherein deleterious path-
ways, such as racemization, may be avoided. Though a
number of examples have been demonstrated in microscale
reactors, these approaches benefit from development in inher-
ently scalable reactors.
The first ACE inhibitor was described by E.R. Squibb and
Sons Pharmaceuticals in 1977 with the disclosure of captopril
1.[3] This successful development initiated intense campaigns in
Our development began by evaluating the amide coupling
of 18 by acid chloride activation in flow (Scheme 1). As an al-
ternative to toxic and otherwise hash chlorinating reagents
such as PCl5, a highly soluble analogue of the Vilsmeir re-
agent 22 was prepared from diethyl formamide and phthalyl
chloride. Activation of fragment 18 with the chlorinating re-
agent was followed by addition of tetrahydroisoquinoline 23.
Quenching of this stream with aqueous base and partitioning
with a membrane phase separator afforded quinapril-OBn 24
in up to 69% yield. However, persistent production of insolu-
ble material attributed to hydrochloride salts prior to the aque-
ous quench prevented sustained performance of the system
and this route was ultimately abandoned.
structure–activity relationship optimization that yielded
a
range of potent and structurally diverse ACE inhibitors.[4] The
presence of an N-substituted l-alanine fragment proved to be
a robust structural motif present in many effective ACE inhibi-
tors.
As shown in Figure 1B, two representative examples of ACE
inhibitor syntheses highlight improvement opportunities in the
manufacturing processes. In 2005, Lupin Ltd. reported the
treatment of fragment 14 with PCl5 to yield the corresponding
acid chloride 15.[2] Isolation of this activated intermediate re-
quired careful handling the stoichiometric POCl3 byproduct
and was followed by amide coupling with 16. The sequence
concluded with a process intensive catalytic hydrogenolysis
As shown in Figure 2, activation of 18 by NCA was subse-
quently investigated. NCAs have found utility in polypeptide
synthesis and their preparation has recently been embodied as
an efficient continuous process, but general application to
stepwise peptide coupling reactions has been limited by a pro-
pensity for undesired oligomerization.[8] It was initially suspect-
ed that in situ IR analysis would be an ideal analytical tool to
monitor the unique carbonyl moieties formed upon NCA cycli-
zation. As expected, two strong IR signals at 1783 and
1854 cmÀ1 appeared upon treatment of 18 with 1.0 equivalent
[a] C. P. Breen, Prof. Dr. T. F. Jamison
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Ave., Cambridge, MA 02139 (USA)
E-mail: tfj@mit.edu
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201904400.
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Figure 1. (A) Captopril and several related ACE inhibitors bearing a similar N-substituted l-alanine fragment. (B) Two common process strategies for activation
of N-substituted l-alanine fragments in the production of perindopril 6 and quinapril 12. (C) Continuous flow approach described herein.
Scheme 1. Initial investigation into amide coupling of 18 and 23 facilitated by acid chloride activation with iminium chloride 22.
of CDI at room temperature under batch conditions. The NCA
signals stabilized within 9 minutes, indicating that 19 could be
formed under mild conditions in reaction times relevant to im-
plementing a continuous process. In the same reaction vessel,
addition of 20 resulted in decay of the anhydride signals. It is
also worth noting that the carbon dioxide generated as a by-
product of amide coupling was detected at 2340 cmÀ1. Most
1
importantly, both H NMR and HPLC-MS analysis showed that
the reaction sequence was not impeded by oligomerization of
18.
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Figure 2. Preliminary experiment showing utility of in situ IR analysis in the amide coupling of 18 and 20.
We subsequently turned our attention towards evaluating
the scope of ACE inhibitors accessible via NCA activation in
batch in order to outline potential residence time regimes in
flow. As shown in Table 1, a range of tBu-protected ACE inhibi-
tors were accessible upon treatment of 19 and 25 with differ-
ent coupling partners. In situ IR monitoring was employed
throughout these trials in order to determine how reaction
times varied across the range of substrates. In general, sec-
ondary amines constrained in five membered rings reacted
with the highest rate and were isolated in the highest yields
(Table 1, entries 1–6). Oxoimidazolidine 27 was a notable ex-
ception to this trend (entry 2) and did not react under stan-
dard conditions presumably due to poorer nucleophilicity. Re-
activity was achieved by generating the potassium salt of 27
after addition of 1.0 equivalent of potassium tert-pentoxide,
which necessitated a solvent switch of the amine solution
from DCM to DMA in order to maintain homogeneity. In the
case of indolapril 35, reaction times could be shortened from
17 to 6 minutes by heating to 458C albeit with a loss of 16%
isolated yield. (entries 4 and 5). In moving to tetrahydroisoqui-
noline derived 20 and 30 (entries 7–10), reaction times at
room temperature were extended up to 120 minutes while still
maintaining good yields. These lengthy reaction times were
both reduced to 60 minutes by applying gentle heat with a
slight loss of isolated yields. Acyclic amino indane 31 proved
to react particularly slowly at room temperature, taking over
8 hours to reach full consumption of 19. Further heating to
658C as well as addition of 20 mol% DMAP resulted in a more
rapid amide coupling while maintaining good isolated yield of
delapril 38 (entry 8).
centrations by examining the 1783 and 1854 cmÀ1 carbonyl
frequencies (see the Supporting Information). The reactions of
amines 26, 28, 29, 20, and 30 with 19 generated by reaction
Table 1. Amide coupling of N-substituted l-alanine fragments 18 and 14
with amino acid derivatives in batch.
Entry[a]
Coupling
Partners
ACE
Inhibitor-OtBu
T [8C]
t [min][b]
Y [%][c]
1
18+26
18+27
18+28
18+29
18+29
14+29
18+20
18+20
18+30
18+30
18+31
enalapril 32
imidapril 33
ramipril 34
23
23
23
23
45
23
23
45
23
45
65
3
3
4
17
6
16
120
55
118
60
150
99
79
96
99
83
92
92
90
94
89
88
2[d]
3
4
5
6
7
8
9
10
11[e]
indolapril 35
indolapril 35
perindopril 36
quinapril 21
quinapril 21
moexipril 37
moexipril 37
delapril 38
[a] All trials performed on 0.89 mmol scale. [b] Reaction endpoints judged
by in situ IR analysis of NCA carbonyl signals. [c] Yields refer to isolated and
spectroscopically pure compounds. [d] Amine was 1m in DMA containing
1.0 equivalent of potassium tert-pentoxide (2m in THF). [e] Amine solution
contained 20 mol% DMAP.
We were able to gain kinetic understanding of the one-pot
procedure by calibration of the IR signal with a sample of 18.
It was shown that the observed IR signal intensity correlated
linearly with molar concentration under relevant reaction con-
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of 18 with CDI were then evaluated on 1.0 mmol scale at am-
bient temperature. Molar reaction kinetics data was generated
by normalizing the reaction times and converting IR signal in-
tensity to molar concentration (Figure 3). Further processing
revealed linear initial rates within the first minute of reaction
(Figure 3 inset). Initial rate values within this time were derived
from linear regression analysis, allowing for direct comparison
of reaction efficiency (see the Supporting Information). The
most rapid coupling was observed during formation of enalap-
ril 32. The initial rates analysis was also able to capture a slight
loss in coupling efficiency in moving from ramipril 34 to indo-
lapril 35, which is likely caused by the increased steric effects
of perhydroindole 29. Lastly, a dramatic decrease in amide cou-
pling rate was observed for tetrahydroisoquinolines 20 and 30.
Table 2. Telescoped continuous synthesis of ACE inhibitors from 18 or 20.
Entry[a] Coupling ACE
Partners Inhibitor·TFA
Coupling T [8C] Coupling tR [min] Y [%][b]
1
18+26 enalapril 2
18+27 imidapril 3
18+28 ramipril 5
18+29 indolapril 7 23
14+29 perindopril 6 23
18+20 quinapril 12 45
18+30 moexipril 13 45
23
23
23
5.6
5.6
5.6
16.7
16.7
45.0
45.0
150.0
88
74
83
82
84
86
81
80
2[c]
3
4
5
6
7
8[d]
18+31 delapril 11
65
[a] Continuous flow experiments were equilibrated for 3 tR before collecting
the crude reaction stream for 60 minutes. [b] Yields refer to isolated com-
pounds after off-line purification. [c] Amine was 1m in DMA containing
1.0 equivalent of potassium tert-pentoxide (2m in THF). [d] Amine solution
contained 20 mol% DMAP.
bered rings were isolated in the highest yield except for imi-
dapril 3 (Entries 1–5). In moving to quinapril 12, moexipril 13,
and delapril 11, yields were generally lower. The throughput of
this compact benchtop reactor was ꢀ500 mghÀ1. In the case
of enalapril 2, for example, 517.8 mg of the API was isolated
from a one-hour collection.
The scalability of this approach was demonstrated by per-
forming the synthesis of enalapril 2 using a Corning Advanced-
Flow Reactor platform. The molar flow rate was scaled to twice
that of the benchtop reactor (Table 2, entry 1) and the system
utilized 8 Low-Flow reactor plates connected in series followed
by a G1 plate for a total internal volume of 12.6 mL and a total
residence time of ꢀ47 minutes (see the Supporting Informa-
tion). By taking advantage of this platform, the throughput of
2 was raised to ꢀ1 ghÀ1 (ꢀ8.8 kgyrÀ1) while maintaining a
similar yield to the custom bench-top reactor (86%). Due to
the well characterized thermal and mass transport properties
of this system, it may be feasible to increase the throughput of
this process by scaling the reactor plate volumes without need
for further reaction optimization.[9]
Figure 3. Amide coupling reaction kinetics with linear initial reaction rate
inset. All trials were performed on 1.0 mmol scale at ambient temperature in
batch by recirculating through a flow IR cell.
With the activation and amide coupling well understood, we
sought to incorporate ester deprotection as a telescoped three
step continuous flow process. A residence time study of the
formation of NCA 19 enabled by calibrated flow IR analysis
was performed in a preliminary experiment aimed at evaluat-
ing the translation of batch kinetics observation to flow (see
the Supporting Information). After passing streams of 18 and
CDI through a helical-type static mixer it was found that
>96% yield of 19 could be achieved in ꢀ9.5 minutes of resi-
dence time, a value in agreement with observations made in
batch. A simple tubular reactor for the fully telescoped process
was then constructed from perfluoroalkoxy (PFA) polymer
tubing, T-mixers, a back-pressure regulator, and a water bath
for heating (Table 2). Amide coupling residence times were
varied in order to accommodate the range of reaction times
observed during reaction scope exploration. This aspect was
not detrimental to ease of operation due to the simplicity of
this continuous tubular reactor. The three-step continuous
flow process resulted in good isolated yields of ACE inhibitor
products starting from either 18 or 14. Similar to the batch
amide coupling results, amine substrates bearing five-mem-
Minimizing formation of therapeutically inactive diketopiper-
azine (DKP) impurities during amide coupling, protecting
group removal, and isolation procedures has motivated a
number of process optimization efforts.[10] Thus, avoiding this
complication was a significant guiding principle of this work.
Applied reaction temperature was the greatest contributing
factor to DKPs observed during this study. Temperatures above
508C often resulted in significant DKP formation as detected
by LCMS analysis of crude reaction mixtures. Even though total
residence times may be reduced by thermal acceleration, elimi-
nating DKP formation was seen as a more important target. A
notable exception to this trend was delapril. Both the tBu-
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ester 38 and final API 11 were more thermally stable than the
other ACE inhibitors.
In summary, a general strategy for synthesizing ACE inhibi-
tors in a fully telescoped three-step continuous flow process
has been established. We initially discovered that an NCA facili-
tated amide coupling approach was more suitable for a contin-
uous process than acid chloride activation. Development of
the NCA approach was expedited by the use of calibrated in
situ IR analysis and greater understanding of kinetic behavior
was gained by initial rates analysis. A key feature of this ap-
proach is the unification of the synthetic process of this class
of important APIs. Future work will focus on select ACE inhibi-
tors that do not bear the commonly employed N-substituted
l-alanine fragment exploited in this strategy.
Acknowledgements
This work was supported by the DARPA Make-It program
under contract ARO W911NF-16-2-0023. CPB is grateful for sup-
port received through the MIT Dean of Science Fellowship. We
also thank Dr. RacheL L. Beingessner (MIT), Dr. Justin Lummiss
(MIT), and Dr. Jon Jaworski (MIT) for helpful discussions and
the Jensen Lab (MIT) for use of Corning equipment.
[5] S. M. Jennings (Warner-Lambert Company LLC), US2004019261A1,
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Jensen, Science 2019, 365, eaax1566.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: ACE inhibitors · amides · anhydrides · kinetics ·
multistep continuous flow synthesis
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Version of record online: && &&, 0000
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COMMUNICATION
&
Kinetics
C. P. Breen, T. F. Jamison*
&& – &&
Continuous Flow Synthesis of ACE
Inhibitors From N-Substituted l-
Alanine Derivatives
An “ACE” in the hole: A range of angio-
tensin converting enzyme inhibitors
were synthesized in continuous flow
using a single synthetic approach in
good overall yields (see scheme). Utiliza-
tion of in situ IR analysis facilitated a
rapid development process and provid-
ed kinetic insight to the key amide cou-
pling step across the set of important
active pharmaceutical ingredients.
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