A continuous flow process using a sequence of microreactors with in-line IR analysis for the preparation of N,N-diethyl-4-(3-fluorophenylpiperidin-4- ylidenemethyl)benzamide as a potent and highly selective δ-opioid receptor agonist

Article abstract of DOI:10.1002/chem.201002147

This article describes the design, optimisation and development of a continuous flow synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4- ylidenemethyl)benzamide, a potent δ-opioid receptor agonist developed by AstraZeneca. The process employs a sequence of flow-based microreactors, with integrated purification employing solid-supported reagents and in-line IR analytical protocols using a newly developed ReactIR flow cell. With this monitoring device, initiation of the fourth input flow stream can be precisely controlled during the synthesis. A four-step flow synthesis of a potent δ-opioid receptor agonist was developed (see scheme), using a continuation of pumping devices in combination with cartridges packed with appropriate scavengers to effect clean delivery of the product. We have also reported the use of in-line ReactIR monitoring to synchronise pumping of a late input stream to coordinate reactive components.

Full text of DOI:10.1002/chem.201002147

DOI: 10.1002/chem.201002147
A Continuous Flow Process Using a Sequence of Microreactors with In-line
IR Analysis for the Preparation of N,N-Diethyl-4-(3-fluorophenylpiperidin-4-
ylidenemethyl)benzamide as a Potent and Highly Selective
d-Opioid Receptor Agonist
Zizheng Qian, Ian R. Baxendale, and Steven V. Ley*[a]
Abstract: This article describes the design, optimisation and development of a con-
tinuous flow synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)-
benzamide, a potent d-opioid receptor agonist developed by AstraZeneca. The
process employs a sequence of flow-based microreactors, with integrated purifica-
tion employing solid-supported reagents and in-line IR analytical protocols using a
newly developed ReactIR flow cell. With this monitoring device, initiation of the
fourth input flow stream can be precisely controlled during the synthesis.
Keywords: flow chemistry
spectroscopy · microreactors · solid-
phase synthesis
·
IR
Introduction
To further demonstrate the advantages of continuous flow
chemistry to produce drug molecules and their derivatives,[8]
we chose to synthesise the olefinic piperidine compound 1
(see below), a novel, exceptionally selective and potent d-
opioid receptor agonist developed by AstraZeneca.[9] Like
all members of the opioid receptor family, agonists for d-
opioid receptors have been shown to exhibit analgesic ef-
fects.[10]However, as was later established, a selective d-
opioid receptor agonist can achieve the desired pain relief
without the side effects associated with other members of
the family (e.g., respiratory depression, dependence liability,
and dysphoria).[11] This discovery has provided the momen-
tum for developing selective nonpeptide d-opioid receptor
agonist.
In 2003, Wei and co-workers published a five-step synthe-
sis of the target molecule 1, with an overall yield of 6%.[9]
Our aim was to improve upon this yield and the efficiency
of the synthesis using flow-based methodologies. We also
wished to determine new methods to overcome some of the
current difficulties encountered in flow chemistry, namely,
the precise control and introduction of additional flow
streams to non-steady state fluid flows. In many operations
The development of flow chemistry has considerably ex-
panded the armoury of chemical processing tools available
to the modern day organic chemists.[1] The impact and sig-
nificance of this technology is reflected by the exponential
increase and by the diverse nature of the synthetic transfor-
mations facilitated by these methods.[2] By comparison to
the conventional batch-mode synthesis, flow chemistry
offers much improved efficiency through telescoped reaction
processes.[3] Moreover, by incorporating solid-supported
scavengers for the removal of by-products,[4] pure products
can be obtained with no need for standard purification pro-
cedures such as aqueous workup, distillation and column
chromatography.[5] Consequently, less solvent is necessary
and reduced amounts of waste materials are generated,
making the procedure more sustainable.[6] Furthermore, any
toxic and potentially hazardous reaction intermediates can
be generated and used in situ within the confines of the
device, allowing much safer handling of chemicals.[7]
the dispersion of
a reaction
[a] Z. Qian, Dr. I. R. Baxendale, Prof. S. V. Ley
Innovative Technology Centre, Department of Chemistry
University of Cambridge, Lensfield Road, Cambridge
CB2 1EW (UK)
plug through diffusion pre-
cludes the precise estimation of
reactants and product eluting
through the system in a multi-
step sequence. Consequently,
the addition of auxiliary reac-
Fax : (+44)1223-336442
E-mail: theitc@ch.cam.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002147.
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Chem. Eur. J. 2010, 16, 12342 – 12348

FULL PAPER
tants delivered by a third or fourth reaction stream is diffi-
cult to control and regulate. In this research a newly devel-
oped ReactIR flow cell was used as a convenient in-line an-
alytical tool for expediting continuous processing. Indeed,
recent work within our group has already demonstrated the
power of this IR monitoring device, and its potential for
solving key issues associated with multi-step reaction se-
quences where knowledge of reagent concentration at all
stages is of paramount importance.[12]
In this new work, we describe the development of a four-
step continuous flow sequence to 1 using the commercially
available Vapourtec R2+/R4 reactor and Mettler-Toledo
ReactIR 45 m system (Figure 1).[13]
Scheme 1. General scheme showing the intermediate structures for the
synthesis of 1.
sulted in blocking of the instruments tubing and valves. By
switching to a solution of iPrMgCl·LiCl with diethylamine,
the precipitation issue was avoided. Solutions of the cooled
iPrMgCl·LiCl (1.16m, 1.5 equiv, ꢀ408C) and a mixture of di-
ethylamine (1.55m, 2.0 equiv) and ester 2 (0.77m, 1.0 equiv)
in THF were loaded into two identical PEEK sample loops
(2 mL internal volume, 0.16 mm i.d.).The two sample loops
were simultaneously injected into the main flow stream
through a T-piece connector at a flow rate of 0.125 mLminꢀ1
per channel. The combined stream was then directed
through a convection flow coil (CFC, 10 mL volume, 1 mm
i.d. polyfluoro acetate, PFA tubing) submerged in a mixture
of MeCN and dry ice, which was maintained at ꢀ408C
giving a residence time of 40 min. The exiting flow stream
from the CFC reactor was then directed into a glass column
(10 mm ꢁ 10 cm)[15]which was packed with a 1:1 mixture of
Quadrapure-benzylamine (QP-BZA, 5 equiv) and Quadra-
pure-sulfonic acid (QP-SA, 5 equiv)[16] to work up the prod-
uct stream and scavenge the residual amine starting material
and base. A second glass column loaded with silica gel
(600 mg) was then employed to trap the magnesium salts
generated during the process. Despite initially poor results
(Table 1), we eventually found the best conditions were to
conduct the reaction at ambient temperature (258C), which
gave the desired product 3 in essentially quantitative yield
(Scheme 2, Table 1).
Moreover, when the amide coupling reaction was con-
ducted at room temperature, the reaction mixture became
bright red in colour (Figure 2), which was not observed at
08C. It was suspected that this could be due to the addition-
al deprotonation of the diarylmethyl proton. To confirm the
colour change was not related to simple the amide coupling
reaction itself, a control reaction was performed with methyl
benzoate under identical condition. In this case, no signifi-
cant colour change was observed during the process. There-
fore, we concluded the amide coupling reaction and depro-
tonation of the ester 2 occurred simultaneously at room
temperature, such that we could then further couple with 1-
Boc-4-piperidone (6), to directly form the key intermediate
4 in a single operation.
Figure 1. Vapourtec R2+/R4 microreactor and Mettler–Toledo ReactIR
45 m.
Results and Discussion
The general synthesis scheme to diarylpiperadine 1 is shown
in Scheme 1, whereby the initial step requires the develop-
ment of an amide bond-forming process (2!3).
First, we attempted to use conditions that were applied in
the reported batch synthesis to generate the diethyl amide
using iPrMgCl at ꢀ408C (Scheme 2, Table 1).[14] However,
this method caused precipitation of magnesium salts and re-
Table 1. Condition screening for the flow synthesis of the amide 3 from
the ester 2.
Grignard reagent
Temp. 1 [8C]
Temp. 2 [8C]
Yield 3 [%]
iPrMgCl
ꢀ40
ꢀ40
ꢀ40
0
25
25
ꢀ40
ꢀ40
0
0
0
0[a]
0
0
40
60
99
0[a]
iPrMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl
25
25
25
[a] Yields could not be obtained for these reactions due to blockage of
the instrument tubing/valves during the reaction.
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S. V. Ley et al.
Table 2. Scavenger screening for 1-Boc-4-piperidone(6).
Scavenger
T [8C]
Recovered 6 [%]
QP-BZA
QP-BZA
MP-TsNHNH2
MP-TsNHNH2
25
60
25
60
99
99
40
0
All reactions were performed using a solution of 6 (2 mmol, 1 equiv) in
THF (2 mL) and 5 equivalents of scavengers.
Boc-4-piperidone (6) was introduced later using a third
pump at 0.25 mLminꢀ1 (Scheme 4). Since the initial stream
of the reaction was brightly coloured, the timing for the sub-
sequent addition could be accurately controlled to meet and
combine with the ketone 6. The resultant flow stream was
then passed through a CFC (10 mL) maintained at ambient
temperature, followed by in-line treatment comprising of
three consecutive columns; 1) QP-SA (3 equiv), 2) MP-
TsNHNH2 (5 equiv) and finally 3) silica gel (600 mg). Un-
fortunately, a yield of only 10% of the desired product 4
was realised using this process, suggesting that the dual de-
protonation had proceeded poorly. To enhance the deproto-
nation, a series of co-solvents were screened (Scheme 4,
Table 3), where 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyri-
midinone (DMPU) gave the best results, yielding 50% of
the desired product 4 after purification by column chroma-
tography.
Scheme 2. Amide coupling reaction in flow.
Figure 2. Bright red colour observed during the amide coupling reaction
at 258C.
Accordingly we optimised the two-step continuous flow
sequence to form the key intermediate 4. Knowing that we
would have to use the 1-Boc-4-piperidone (6) in excess; we
began by scrutinising suitable scavengers for removal of this
excess reagent (Scheme 3, Table 2). While QP-BZA was in-
effective in this process, polystyrene sulfonyl hydrazide resin
(MP-TsNHNH2, 5 equiv)[17] performed well essentially re-
moving all the piperidone 6 upon heating at 608C.The re-
agent could then be used in a cartridge format to progress
the synthesis of the key intermediate 4.
We used the new conditions for the amide coupling reac-
tion but increased the mole equivalents of diethylamine
(from 2.0 to 2.5) and iPrMgCl·LiCl (from 1.5 to 2.0) for
complete deprotonation of the intermediate amide 3. The 1-
Scheme 4. Continuous flow synthesis of the key intermediate 4.
The next step of the process, the dehydration of inter-
mediate 4 was accomplished using the Burgess reagent (7).
The procedure required solutions of the Burgess reagent
(3.0m, 6.0 equiv) in CH2Cl2 and alcohol 4 (0.5m, 1.0 equiv)
in THF to be loaded into two separate PEEK sample loops
Scheme 3. Scavenger screening for 1-Boc-4-piperidone (6).
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A Continuous Flow Process Using Microreactors
FULL PAPER
Table 3. Condition screening for the continuous flow synthesis of the key
intermediate 4.
Co-solvent
Yield 3 [%]
Yield 4 [%]
THF
HMPA
dimethoxymethane
DMF
DMPU
85
50
0
99
45
10
48
0[a]
0
50
[a] The yield could not be obtained for this reaction due to precipitation
occurring during the reaction.
(1 mL internal volume).
A
solvent flow rate of
0.25 mLminꢀ1 was used to introduce the two compounds
and combine their pathways at a standard T-piece mixer
(Scheme 5). The reaction stream was then passed through a
CFC (10 mL volume), which was heated at 608C, followed
by a column loaded with a mixture of QP-SA (3 equiv) and
QP-BZA (5 equiv) to sequester the excess Burgess reagent
and associated by-products. The resultant solution was then
concentrated in vacuo to give the desired product alkene 5
in near quantitative yield (99%).
Scheme 6. Homogeneous Boc deprotection in flow.
shown in Scheme 7, a solution of protected material 5 (0.5m,
1.0 equiv) in THF was therefore passed through a heated
column (608C) of QP-SA (5.0 equiv), enabling the depro-
tected amine 1 to be concurrently protonated and retained
within the acidic column. The column was allowed to cool
to room temperature, and the product could then be later
released by eluting the column with a solution of ammonia
in MeOH (2.0m, 5 equiv).This “catch and release” proce-
dure proved very reliable for delivering high pure product
requiring only concentration in vacuo to yield the desired
product 1 (92%).
Scheme 5. Dehydration reaction in flow.
The final stage Boc deprotection was well precedented,[9]
hence our initial effort involved conducting the reaction fol-
lowing the reported batch conditions. Two solutions, one
comprising of trifluoroacetic acid (TFA) in CH2Cl2 (1.0m,
2.0 equiv) and the second containing the Boc-protected
amide 5 in THF (0.5m, 1.0 equiv) were loaded into PEEK
sample loops (1 mL internal volume). These solutions were
then introduced at 0.50 mLminꢀ1 per channel to the main
stream via a T-piece connector (Scheme 6). The reaction
stream was progressed through a CFC (10 mL volume),
which was held at 258C, and then purified by passage
through a column of QP-BZA (10 equiv) allowing isolation
of the target molecule 1 in an acceptable 94%yield.
Scheme 7. Heterogeneous Boc deprotection in flow.
Both methods gave the desired product in comparable
yield. However, for the continuous flow synthesis, we decid-
ed in favour of the heterogeneous route. This was mainly
due to the fact that with one less chemical being introduced
in the reaction sequence, the setup and control of the over-
all system would be much simpler.
Having completed the flow synthesis of the target mole-
cule in three phases, we aspired to develop the reaction into
a single flow sequence. The first problem we encountered
involved synchronising the introduction of a fourth reaction
stream (the Burgess Reagent). This issue was overcome by
using the ReactIR 45 m flow cell (Figure 1, Scheme 8). To
Previous work within the group, however, suggested the
Boc deprotection could be performed using a heterogeneous
acid catalysts, such as QP-SA, at elevated temperatures. As
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S. V. Ley et al.
Scheme 8. Continuous flow synthesis of the target molecule 1.
establish the in-line monitoring system, we first recorded the
IR spectrum of all the solvents and reagents involved in
these reactions.[18] Next, the intermediate 4 was scanned and
a characteristic stretching frequency between 1690 and
1700 cmꢀ1 identified (Figure 3). Therefore, by recording the
volume (0.5 mLminꢀ1 ꢁ 20 min=10 mL) of Burgess reagent
needed to perform the reaction.
With all these results in hand, we were finally able to
complete the continuous flow synthesis of the target mole-
cule as an integrated process (Scheme 8). As previously de-
scribed solutions of iPrMgCl·LiCl (1.16m, 2.0 equiv) and a
mixture of DMPU, diethylamine (1.45m, 2.5 equiv) and the
ester 2 (0.58m, 1.0 equiv) in THF were combined at a T-
piece connector. The resultant mixture was flowed through
a CFC reactor (10 mL, 258C) before being merging with a
third stream of the 1-Boc-4-piperidone (6, 0.33m, 1.2 equiv)
via a second T-piece mixer. The reaction stream was then di-
rected through a second CFC (10 mL, 258C), followed by
three columns containing in order of QP-SA (3 equiv), MP-
TsNHNH2 (5 equiv) and silica gel (600 mg). The exiting
stream then entered the ReactIR flow cell, and as soon as
the indicative fingerprint signal was detected (i.e., IR
stretching frequency 1690–1700 cmꢀ1, Figure 4), the fourth
Figure 3. Recorded IR spectrum of the key intermediate 4.
intensity of IR absorption at
this spectral region over the
time of the reaction, we were
able to directly synchronise the
introduction of the fourth input
stream containing the Burgess
reagent (Figure 4). Moreover,
we were able to determine the
extent of dispersion of com-
pound 4 during our initial ex-
periment, and hence calculate
Figure 4. Intensity of IR absorption for the amide stretching frequency for key intermediate 4over the time of
the exact concentration and the continuous flow synthesis.
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A Continuous Flow Process Using Microreactors
FULL PAPER
(red) and was then directed through a CFC (10 mL) attached via a glass
jacket to the R4 unit, which was maintained at ambient temperature,
giving a residence time of 40 min. Towards the end of this sequence,
sample loop 3 was switched in-line with a switching valve to introduce 6
into the main flow stream via a T-piece connector at a flow rate of
0.25 mLminꢀ1. The resultant stream was then passed through a second
CFC (10 mL) maintained at room temperature, followed by in-line treat-
ment comprising of three consecutive columns; 1) QP-SA (580 mg,
1.74 mmol, 3 equiv), 2) MP-TsNHNH2 (1.0 g, 2.9 mmol, 5 equiv) and fi-
nally 3) silica gel (600 mg).The exiting stream then entered the ReactIR
flow cell, and as soon as the indicative fingerprint signal was detected
(i.e., IR stretching frequency 1690–1700 cmꢀ1, Figure 4), the 4th sample
loop was switched in-line, allowing the Burgess reagent to join the main
reaction stream. The reaction mixture was pumped through a third CFC
(10 mL, 608C) before entering a column loaded with a mixture of QP-SA
(580 mg, 1.74 mmol, 3 equiv) and QP-BZA (530 mg, 2.9 mmol, 5 equiv).
In the end, a heated column of QP-SA (1 g, 2.9 mmol, 5 equiv, 608C) was
used to deprotect and catch the target molecule. The acidic column was
then allowed to cool to ambient temperature, and elution of which using
a solution of NH3 in MeOH (3.5 mL, 7 mmol, 6 equiv) completed the
synthesis in a continuous fashion, and gave the desired product 1 as a
yellow oil (74 mg, 35%).Rf =0.03 (EtOAc/hexane 2:1); LC tR =
2.728 min; 1H NMR (500 MHz, CDCl3): d=7.29 (d, J=8.0 Hz, 2H; Ar-
H), 7.24 (td, J=7.8 Hz, 6.1 Hz, 1H; Ar-H), 7.11 (d, J=8.0 Hz, 2H; Ar-
H), 6.88–6.91 (m, 2H; Ar-H), 6.80 (dt, J=9.7 Hz, 1.8 Hz, 1H; Ar-H),
3.52 (brs, 2H; N-CH2), 3.27 (brs, 2H; N-CH2), 2.90 (qn, J=5.8 Hz, 4H;
piperidine N-CH2), 2.31 (t, J=5.7 Hz, 4H; piperidine CH2), 2.07 (brs,
1H; NH), 1.23 (brs, 3H; CH3), 1.11 ppm (brs, 3H; CH3); 13C NMR
and final input stream was started, allowing the Burgess re-
agent (0.34m, 6 equiv) to join the main reaction stream. The
reaction mixture was pumped through a third CFC (10 mL,
608C) before entering a column loaded with a mixture of
QP-SA (3 equiv) and QP-BZA (5 equiv). Finally, a heated
column of QP-SA (5 equiv) was used to deprotect and catch
the target molecule. Any unreacted amide 3 from the first
two steps was simply pumped to waste, while all the key in-
termediate 4 had already been cleanly converted to the de-
sired product 1. Elution of the acidic column using a solu-
tion of NH3 in MeOH (2.0m, 6 equiv) completed the synthe-
sis in a continuous fashion, and gave the product 1 in 35%
overall yield and in high purity over the four steps.
Conclusion
In summary, we have developed a four-step flow synthesis
of a potent d-opioid receptor agonist. In this work, we have
used a combination of pumping devices together with car-
tridges packed with appropriate reagents or scavengers to
effect clean delivery of the product. Importantly, we have
also reported the use of in-line ReactIR monitoring to syn-
chronise pumping of a late input stream to coordinate reac-
tive components. We believe this flow chemistry sequence
further demonstrates the power of these methods for multi-
step, multi-component coupling processes leading to func-
tional molecules with potential commercial and healthcare
benefits.
(125 MHz, CDCl3): d =171.1 (s; C=O, benzamide), 162.6 (d, J
244.6 Hz; Ar-F), 144.2 (d, J(C,F)=7.3 Hz; Ar), 142.7 (s; Ar), 137.5 (s;
C=C), 135.4 (s; Ar), 134.2 (s; piperidine C=C), 129.7 (s; Ar), 129.5 (d,
(C,F)=8.5 Hz; Ar), 126.3 (s; Ar), 125.6 (d, J(C,F)=2.8 Hz; Ar), 116.7
(d, J(C,F)=20.8 Hz; Ar), 113.4 (d, J(C, F)=20.9 Hz; Ar), 48.3 (s; piperi-
ACHTUNGTRENNUNG(C,F)=
AHCTUNGTRENNUNG
J
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
dine N-CH2), 43.3 (s; N-CH2), 39.2 (s; N-CH2), 33.2 (s; piperidine CH2),
14.2 (s; CH3), 12.8 ppm (s; CH3); 19F NMR (400 MHz, CDCl3): d=
ꢀ113.77 ppm (Ar-F); IR (film): nmax =3302 (brw, NH), 3245, 2968, 2934
(m, CH), 1623 (s, C=O, amide), 1609, 1580, 1473, 1459, 1429, 1382, 1365,
1312, 1288, 1263, 1220, 1138, 1096, 1013, 969, 943, 879, 855, 805, 787,
763 cmꢀ1; ESI MS: m/z: 367.20 [M+H]+; HRMS (+ESI): m/z: calcd for
C23H27N2OF: 367.2186, found: 367.2186 [M+H]+.
Experimental Section
General: Infrared spectra were recorded using a Perkin–Elmer One FT-
IR spectrometer fitted with an ATR sampling accessory as either liquid
films or dilute solutions in spectroscopic grade chloroform or dichlorome-
thane. The intensity of the signals is designated by the following abbrevi-
ations: s, strong; m, medium; w, weak; br, broad; sh, sharp.1H NMR spec-
tra were recorded on Bruker DPX-500 (500 MHz) instrument and
19F NMR spectra were recorded on a Bruker DPX-400 (400 MHz) instru-
ment as dilute solutions in deuterated chloroform unless otherwise
stated. 13C NMR spectra were recorded at 125 MHz on Bruker DPX-500
instrument with CDCl3 as the solvent. The chemical shifts are reported
relative to residual chloroform as an internal standard, and all coupling
constants, J, are reported in Hertz (Hz).LC-MS analysis was performed
on an Agilent HP 1100 series chromatograph (Mercury Luna 3 m C18 (2)
column) attached to a Waters ZQ2000 mass spectrometer with ESCi ioni-
zation source in ESI mode. Mass spectra were obtained on a Kratos-
QTQF spectrometer using electrospray ionisation (+ESI) or LCT Pre-
mier spectrometer by Waters using Micromass MS software by electro-
spray ionisation (+ESI) at the Department of Chemistry, Cambridge.
Acknowledgements
We gratefully acknowledge financial support from the Royal Society (to
I.R.B.), the Cambridge Overseas Trust (to Z.Q.) and the BP endowment
(to S.V.L.). We would also like to thank AstraZeneca for support and
helpful discussion concerning this research.
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Procedure for the continuous flow synthesis of compound 1: A solution
of iPrMgCl·LiCl in THF (1.16m, 1.16 mmol, 1 mL, 2.0 equiv) and a mix-
ture of diethylamine (0.15 mL, 1.45 mmol, 2.5 equiv), DMPU (0.4 mL)
and the ester 2 (142 mg, 0.58 mmol, 1.0 equiv) in dry THF (0.4 mL) were
loaded into two 1 mL sample loops (sample loop 1 and 2). At the mean-
time, solutions of 6 (139 mg, 0.70 mmol, 1.2 equiv) in dry THF (1.9 mL)
and the Burgess reagent (7) (1.66 g, 6.96 mmol, 6.0 equiv) in dry CH2Cl2
(10 mL) were loaded into sample loop 3 (2 mL) and 4 (10 mL) respec-
tively. To initiate, sample loops 1 and 2 were simultaneously injected into
the main flow stream via
a T-piece connector at a flow rate of
0.125 mLminꢀ1 per channel. The combined stream was brightly coloured
Chem. Eur. J. 2010, 16, 12342 – 12348
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S. V. Ley et al.
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pound can be found in the Supporting Information.
Received: July 27, 2010
Published online: September 21, 2010
12348
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