A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets

Article abstract of DOI:10.1039/c7cc03584e

We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 μL. The breadth of compatible chemistries is successfully demonstrated and the desired products are characterized, isolated, and collected online by preparative HPLC/MS/ELSD.

Full text of DOI:10.1039/c7cc03584e

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2017, DOI: 10.1039/C7CC03584E.
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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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Segmented Flow Platform for On‐Demand Medicinal Chemistry
and Compound Synthesis in Oscillating Droplets
Ye‐Jin Hwang,†a, b Connor W. Coley,†a Milad Abolhasani,c Andreas L. Marzinzik,d Guido Koch,d
Received 00th January 20xx,
Accepted 00th January 20xx
Carsten Spanka,d, Hansjoerg Lehmannd and Klavs F. Jensen*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report an automated flow chemistry platform that can
efficiently perform wide range of chemistries, including
a
single/multi‐phase and single/multi‐step, with a reaction volume of
just 14 uL. The breadth of compatible chemistries are successfully
demonstrated, and desired products are characterized, isolated,
and collected online by preparative HPLC/MS/ELSD.
Drug discovery today faces enormous challenges, one of
those being the increasing pressure to deliver a steady stream
of active compounds in increasing numbers and shorter
timelines. Rapid iterations of design, synthesis and screening
are therefore paramount for efficient optimization of lead
molecules in medicinal chemistry.1 Recently, impressive
advances have been made in automation2, miniaturization, and
high‐throughput methodologies (e.g. biological screening3),
shifting the bottleneck toward the synthesis‐step. Increasing
transfer of these technologies to more complex and diverse
organic synthesis applications resolves this and allows more
economical and environmentally benign access to compounds
with less amount of building blocks, equipment, manipulation,
and most importantly decreased cycle times.4 This evolution has
furthermore been facilitated by recently developed IT
applications for the optimization of reaction conditions and
automated conduction of multi‐parallel chemistry experiments
(e.g. data capturing in electronic lab note books, design of
experiments and machine learning).5
Fig. 1. Schematic of the automated droplet‐based medicinal chemistry platform. PS:
phase sensor; PD: photodetector. Dashed lines indicate PC communication, gray lines
correspond to optical fibers for the LED and photodetector, and solid black lines
correspond to fluoropolymer tubing for the delivery and routing of liquid droplets.
receptor‐selective ligands.8 Such systems have been validated
against a set of known DPP4‐ and BACE1‐inhibitors as well
demonstrating rapid iterative structure‐activity relationship
generation.9
Developments in flow chemistry allow for process
intensification and improved control of the space‐time
environment. Reactions using highly reactive starting materials
or requiring high temperature / pressure conditions can now be
conducted with higher reproducibility and safety than
previously in batch mode. The improved parameter space,
enhanced heat and mass transfer rates, high surface to volume
ratio and scalability makes the application of flow chemistry10
and microfluidics11 very appealing to the synthetic chemist.
Here, we report an automated segmented flow screening
technology that enables the generation of data for series of
small focused libraries of lead compounds rapidly. The
technology allows precise control of reaction temperature and
residence time for each experiment – run in single microliter‐
scale droplets – individually. The automation and control
strategy further enables high reproducibility and theoretically
unlimited residence time with similar mixing and mass transfer
characteristics, as well as demonstrably low carryover between
At present, this trend is manifested also in medicinal
chemistry laboratories.6 Fully automated platforms utilizing
used for the discovery of novel Abl kinase inhibitors7 and 5‐HT2B
a. Department of Chemical Engineering, Massachusetts Institute of Technology, 77
Massachusetts Avenue, Cambridge, MA 02139, United States Address here.
b. Department of Chemical Engineering, Inha University, 100 Inha‐ro, Nam‐gu,
Incheon 22212, South Korea.
c. Department of Chemical and Biomolecular Engineering, North Carolina State
University, 911 Partners Way, Raleigh, NC 27695, United States
d. Novartis Institutes for BioMedical Research, Novartis Campus, CH‐4056 Basel,
Switzerland
† These authors contributed equally.
‡ Electronic Supplementary Information (ESI) available: System set‐up, synthesis in
batch, HPLC chromatograms, NMR spectra, calibration curves, characterization of
on‐line injection. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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consecutive reactions. The use of an oscillatory flow reactor
effectively decouples flow rate and residence time. Moreover,
it enables multi‐phase and multi‐step reactions. Our platform
design with off line biological testing ensures maximal
adaptability towards different assay formats.
As a demonstration of this chemistry platform, 36 examples
of frequently used N‐X bond forming reactions using typical
small‐molecule building blocks are used to prepare a small
compound library. In addition, a representative multi‐phase
Suzuki‐Miyaura cross coupling reaction and multi‐step synthesis
of diclofenac are successfully performed. Products are isolated
using an online analytical HPLC/MS/ELSD equipped with a
fraction collector. The collected quantity of purified final
product depends on the reaction concentration and yield, but is
typically between 50 and 500 ug. Product collection in a vial‐ or
plate‐based format enables the straightforward integration of
physical or biological assays downstream.
Scheme 1. “Training Set”: Selected building blocks for four different N‐X bond forming
reactions to prepare a 36‐member compound library.
rinse solution droplets (syringe 2), also propelled through the
system by gas (syringe 3), to minimize carryover between runs
(Fig. S1). The overall cycle time is the larger of the HPLC method
run time and 10‐15 minutes, which consists of the rinsing time,
sample preparation time, droplet motion time outside of the
reactor, and reaction time. Automation provides excellent
reproducibility between runs, beyond what could be achieved
in traditional batch synthesis (Fig. S2 and S3). The software also
allows for multistep reactions where each step has a distinct
temperature and residence time, and where online injections
(through syringe 4 or syringe 5) are performed between steps.
Nitrogen‐containing organic compounds are attractive
bioactive molecules, and thus N‐X bond forming reactions are
important for the preparation of many pharmaceutically active
molecules and prevalent in medicinal chemistry.12 Four most
representative classes of N‐X bond forming reactions in
medicinal chemistry, including nucleophilic aromatic
substitution (SNAr), sulfonylation, acylation, and reductive
amination, were used to prepare a small combinatorial
compound library. As shown in Scheme 1, three amines,
The platform, shown schematically in Fig. 1, prepares and
runs reactions sequentially according to a user‐defined queue
where conditions are pre‐defined. Reagents are withdrawn
from a vial rack of stock solutions using a computer‐controlled
liquid handler and syringe pump (syringe 1), mixed inside the
liquid handler needle, and injected into a 14 uL sample loop. The
droplet is transferred to the main system flowpath, consisting
of fluoroethylene propylene (FEP) tubing filled with 100 psig
argon. An automated syringe pump (syringe 3) controls the
motion of the liquid droplet within the gas‐filled tubing by
infusing pressurized gas, which propels the droplet forward to
the first T‐junction. If specified, another syringe pump (syringe
4) injects an additional reagent into the reaction droplet prior
to entering the oscillatory flow reactor (OFR). Inside the horse‐
shoe shaped OFR, which is heated to the specified reaction
temperature using embedded cartridge heaters, the reaction
droplet is kept in constant motion by reversing the direction of
flow in response to optical detection of the droplet at the
reactor inlet or outlet. The use of gas as a carrier fluid, rather
than a fluorinated oil, eliminates the issue of carrier fluid
miscibility with organic solvents at high temperature. After the
desired residence time, the droplet exits the reactor and is
optionally quenched (syringe 5) before filling an 8 uL sample
loop and being sent to an HPLC/MS/ELSD for analysis and
product collection by UV or MS triggered fraction collection. The
remainder of the droplet empties into a pressurized waste
vessel. The size of the sample loop can be modified if needed.
The system supports reaction temperatures up to 210 °C,
above which the fluoropolymer tubing begins to soften. By
operating the platform at elevated pressures (100 psig),
reactions can be conducted under conditions which exceed
solvents’ boiling points at atmospheric pressure. With the
optical feedback enabled by an LED‐photodetector pair
spanning the reactor inlet and outlet, a droplet can be kept
oscillating for an indefinite amount of time (demonstrated up
to 16 hours). The OFR is designed to enclose fluoropolymer
tubing that provides chemical compatibility. An extensive
cleaning procedure is performed between each reaction to
clean the liquid handler needle and fully flush the system with
a series of
including benzylamine (
a), 1‐phenylpiperazine (
b), and 4‐
methoxyaniline ), which constitute a
(
c
primary amine,
secondary amine, and aniline, respectively, were coupled with
heteroaryl halides, sulfonyl chlorides, carboxylic acids, and
aldehydes to give a total of 36 reactions. Each reaction is
screened at various concentrations, solvents, temperatures,
and residence times to achieve the semi‐optimized reaction
conditions; those parameters and resulting conversions are
summarized in Table 1. All products were successfully isolated
by fraction collector, and confirmed by MS.
Nine SNAr reactions were run in N‐methyl‐2‐pyrrolidone
(NMP) as a solvent with no additional Brønsted base catalyst.
Depending on the reactivity of substrates, resulting conversions
varied in the range of 12.8 – 96.2%. Among the three tested
amines, reactions with amine
(30.3 – 36.1%) due to its weak nucleophilic reactivity, and no
reaction was observed with substrate even after 20 minutes
c showed the lowest conversions
3
of reaction at 140 ˚C. SNAr reactions reached chemical equilibria
and the resulting saturated conversions exhibited strong
dependence on the reaction temperature. As an example,
saturated conversions for the reaction forming a2 at different
reaction temperatures of 40 ˚C, 80 ˚C, and 120 ˚C were 24.1%,
46.9%, and 74.0%, respectively, after 15 – 20 minutes of
residence time (Fig. S4).
All sulfonylation products were obtained with short
residence times (<10 min.), high conversion, and no significant
2 | J. Name., 2012, 00, 1‐3
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even after 45 minutes of reaction at 120 ˚C. All acylations were
performed as a single reaction step; no significant difference
was observed when run as a two‐step reaction by pre‐reacting
carboxylic acid, HATU, and DIEA for 5 minutes at 60 ˚C prior to
the addition of amine. We note that for acylation reactions
Table 1. Summary of conditions and conversions for 36 reactions.
Prod.
Eq.[a]
4
2
4
4
1
2
2
2
4
4
4
4
4
4
4
4
4
4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Conc. [M][b]
0.02
0.03
0.02
0.02
0.04
0.03
0.03
0.03
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.08
0.08
0.08
0.08
0.08
0.08
0.08
0.08
0.08
0.1
Solvent
T [oC]
150
120
140
140
70
t [min]
15
20
15
20
10
15
20
20
20
5
Conv. [%][c]
41.6
74.0
12.8
96.2
53.6
64.6
36.1
30.3
‐
a1
NMP
a2
NMP
a3
NMP
using aniline
c, yields were calculated based on an HPLC
b1
NMP
calibration curve (Fig. S5) using pure products instead of
b2
NMP
conversion due to irresolvable peak overlap of
reagents.
c with other
b3
NMP
140
140
140
140
100
25
c1
NMP
Lastly, reductive aminations were screened to identify
suitable reagent and solvent combinations. Acetic acid (1 eq.)
was also added to facilitate the imine formation. In order to
prevent clogging, tetrabutylammonium borohydride (n‐
Bu4NBH4), readily soluble in organic solvents, was selected with
c2
NMP
c3
NMP
a4
NMP
92.4
100
a5
NMP
1
a6
NMP
120
100
100
100
120
25
10
5
93.5
100
dichloroethane (DCE) as
conversions of 70.3 – 93.2% were achieved for the reactions
with amine and amine at 70 ˚C after 15 to 30 minutes of
residence time, while showed much lower conversions in the
range of 30.8 – 78.5% at same reaction conditions (Fig. S6,). The
difference in the performance of amines , and might be
attributed to the weak strength of as a nucleophile compared
a solvent. With n‐Bu4NBH4,
b4
NMP
b5
NMP
5
100
a
b
b6
NMP
5
100
c
c4
NMP
5
62.6
100
c5
NMP
5
a
,
b
c
c6
NMP
120
60
10
10
10
10
15
5
100
c
a7[d]
a8[d]
a9[d]
b7[d]
b8[d]
b9[d]
c7[d]
c8[d]
c9[d]
a10[f]
a11[f]
a12[f]
b10[f]
b11[f]
b12[f]
c10[f]
c11[f]
c12[f]
DMA
100
to other amines. The best results were achieved by using
sodium cyanoborohydride (NaBH3CN) as a reducing agent in a
2:3 DCE:methanol co‐solvent. The co‐solvent system was
chosen to mitigate the limited solubility of the reducing reagent
and prevent precipitation during the reaction. With NaBH3CN
as the reducing agent, the conversions were in the range of 74.5
– 95.2% for all substrate combinations.
DMA
60
100
DMA
60
100
DMA
60
87.3
73.9
88.8
92.7[e]
98.0[e]
98.0[e]
87.9
95.7
94.4
83.3
95.2
86.7
74.5
89.1
79.5
NMP
120
60
DMA
5
DMA
60
10
10
10
10
10
10
10
10
10
20
20
20
Palladium‐catalyzed multi‐phase Suzuki‐Miyaura cross‐
DMA
60
coupling reactions are extensively used as the main C‐C bond‐
DMA
60
9b]
forming reactions in medicinal chemistries.[9a,
The
DCE:MeOH
DCE:MeOH
DCE:MeOH
DCE:MeOH
DCE:MeOH
DCE:MeOH
DCE:MeOH
DCE:MeOH
DCE:MeOH
65
conventional unidirectional screening systems are not well‐
suited for interfacial catalytic reaction due to the limited
available interfacial area between two immiscible phases. In
our screening platform, however, the oscillatory flow reactor
generates large inter and intra‐phase mass transfer for multi‐
phase reactions as the aqueous phase passes through the
organic phase (Fig. 2a).[14]
Suzuki‐Miyaura couplings of 2‐chloropyridine with two
boronic acids (phenylboronic acid and 3‐thienylboronic acid)
using XPhos Pd G3 as a catalyst demonstrate efficient multi‐
phase reaction screening (Fig. 2b). Complete movement of the
aqueous segment (potassium phosphate (K3PO4) solution in DI
water) from one end to the other end of the organic segment
(tetrahydrofuran (THF)) was observed with a carrier gas flow
0.1
65
0.1
65
0.1
65
0.1
65
0.1
65
0.1
65
0.1
65
0.1
65
[a] Equivalents of amine with respect to the coupling partner. [b] Concentration of the
coupling partner. [c] Conversion is with respect to the coupling partner as the limiting
reagent. [d] HATU (1 eq.) and DIEA (4 eq.) were added. [e] Calculated yield. [f] Acetic acid (1
eq.) and NaBH3CN solution in 2:3 DCE:MeOH co‐solvent (4 eq.) were added.
byproduct formation. The reaction between
a
and
velocity of 1200
L/min. Both reactions showed over 80%
benzenesulfonyl chloride even proceeded at room
(5)
chromatographic yield in 5 minutes of residence time. The yield
was gradually enhanced as residence time increased, and the
reactions were completed after 10 to 15 minutes (Fig. 2c and
2d). Equivalent batch reactions performed under vigorously‐
stirred conditions compared well with those in the OFR
screening system (Table S1), confirming that the OFR provides
sufficiently high mass transfer for this reaction to be in the
kinetically‐limited regime. The few large differences were likely
caused by irregular/uncontrolled physical magnetic stirring in
batch vessels.
temperature and gave full conversion of
(single pass in the reactor).
Acylations were performed with a coupling reagent (1‐
[Bis(dimethylamino)methylene]‐1H‐1,2,3‐triazolo[4,5‐
b]pyridinium‐3‐oxidhexafluorophosphate) (HATU) (1 eq.) and a
base N,N‐diisopropylethylamine (DIEA) (4 eq.) in
dimethylacetamide (DMA) as a solvent. HATU is known to
generate an active ester of a carboxylic acid efficiently.[13] With
HATU, high conversions in the range of 73.9 – 100% were
achieved at a relatively mild temperature of 60 ˚C and a short
residence time, while no reaction was observed without HATU
5 in less than 1 min
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demonstrably low carryover (< 0.5%) and high reproducibility.
Moreover, it extends the range of compatible chemistries from
single‐phase/single‐step reactions to the multi‐phase/multi‐
step reactions which are traditionally incompatible with
conventional microreaction systems.
We thank the Novartis MIT Center for Continuous
Manufacturing for funding this research. CWC thanks the
National Science Foundation Graduate Research Fellowship
Program for support under Grant No. 1122374.
Notes and references
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Fig. 2. (a) Illustration of multi‐phase segmented flow in the oscillatory flow reactor. (b)
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yields of (c) reaction phenylboronic acid and (d) reaction with 3‐thenylboronic acid in
batch and in OFR under argon at 65 ˚C.
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(diclofenac).
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As a final demonstration of the platform’s flexibility, we
demonstrate the multi‐step synthesis of the 2‐(2‐((2,6‐
dichlorophenyl)amino)phenyl)acetic acid, the nonsteroidal anti‐
inflammatory drug (diclofenac) (Fig. 3). The two‐step diclofenac
synthesis15 involves a Buchwald‐Hartwig amination followed by
cleavage of a tert‐butyl ester performed at distinct reaction
temperatures of 90 ˚C and 40 ˚C, respectively, with residence
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precatalysts were tested. The highest conversion of 41.8%
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bromophenyl)acetate) was achieved with precatalyst Sphos Pd
G4. The achieved conversion was comparable to the similarly
performed batch reaction which showed 45.8% conversion at
90 ˚C for 20 minutes. It was also comparable with reported
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After the first reaction, 14 µL acetonitrile with 0.1 vol% of formic
acid was injected into the crude reaction mixture at the online
injection junction (Fig. 1). The cleavage reaction showed near‐
100% conversion, and the final product diclofenac was isolated
and confirmed by MS (Fig. S9) and 1H NMR (Fig. S10 and S11).
In conclusion, we report a droplet‐based automated
synthesis platform for efficient reaction screening, small‐scale
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chemistries at the ~100
g scale, ideal for lead optimization.
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This new technology allows seamless integration of synthesis,
12564.
purification, and analysis on
a microliter scale with
4 | J. Name., 2012, 00, 1‐3
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