Understanding the Alkylation of a Phenol by 1-(3-Chloropropyl)pyrrolidine: Evidence for the Intermediacy of an Azetidinium Ion

Article abstract of DOI:10.1021/acs.joc.8b02458

The final synthetic step in the synthesis of cediranib, AZD2171, 1, is the alkylation of a phenol with an alkyl halide to generate an ether. Our need to understand and control the formation of synthetic impurities generated in this step of the synthesis led us to investigate the kinetics and mechanism of the alkylation of indolphenol, 2, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol, by chloropyrrolidine, 3, 1-(3-chloropropyl)pyrrolidine. Studies in 1-methyl-2-pyrrolidinone (NMP) established that the active alkylating agent is the azetidinium ion, 4, 4-azoniaspiro[3.4]octane, formed via a slow intramolecular cyclization reaction of chloropyrrolidine, 3. The azetidinium ion was isolated as its tetraphenylborate salt from water by heating 3 in the presence of aqueous potassium tetraphenyl borate, and its competence as an intermediate was demonstrated by its fast reaction with 2 to yield cediranib, 1.

Full text of DOI:10.1021/acs.joc.8b02458

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Understanding the Alkylation of a Phenol by 1‑(3-
Chloropropyl)pyrrolidine: Evidence for the Intermediacy of an
Azetidinium Ion
Ian W. Ashworth,*,† Lai C. Chan,† Brian G. Cox,† Ian M. McFarlane,† and Andrew R. Phillips‡
†Pharmaceutical Technology & Development, AstraZeneca, S41/11 Etherow, Silk Road Business Park, Macclesfield, SK10 2NA,
United Kingdom
‡Early Product Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Silk Road Business Park, Macclesfield,
SK10 2NA, United Kingdom
S
* Supporting Information
ABSTRACT: The final synthetic step in the synthesis of cediranib, AZD2171, 1, is
the alkylation of a phenol with an alkyl halide to generate an ether. Our need to
understand and control the formation of synthetic impurities generated in this step
of the synthesis led us to investigate the kinetics and mechanism of the alkylation of
indolphenol, 2, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-
ol, by chloropyrrolidine, 3, 1-(3-chloropropyl)pyrrolidine. Studies in 1-methyl-2-
pyrrolidinone (NMP) established that the active alkylating agent is the azetidinium
ion, 4, 4-azoniaspiro[3.4]octane, formed via a slow intramolecular cyclization
reaction of chloropyrrolidine, 3. The azetidinium ion was isolated as its
tetraphenylborate salt from water by heating 3 in the presence of aqueous
potassium tetraphenyl borate, and its competence as an intermediate was
demonstrated by its fast reaction with 2 to yield cediranib, 1.
on lower levels of impurities in the isolated product, was
identified as the likely cause of the slower reaction upon scale
up.
INTRODUCTION
■
AZD2171, cediranib, 1, is an inhibitor of VEGF for the
treatment of solid tumors.1,2 The final synthetic step in the
synthesis alkylates Indolphenol, 2, with chloropyrrolidine (1-
(3-chloropropyl)pyrrolidine), 3, at elevated temperatures in
NMP (1-methyl-2-pyrrolidinone) in the presence of K2CO3
(Scheme 1).3 When scaling this process up, it was observed
that the reaction time increased relative to the laboratory
process and that elevated levels of an impurity were formed.
The formation of cediranib, 1, by the alkylation of an
aryloxide with an alkyl halide is an example of the classical
Williamson ether synthesis.4 As such, we expected the reaction
to be a simple bimolecular substitution reaction,5 but an
examination of preliminary reaction profile data showed the
reaction time to be independent of the reactant concentration.
This behavior is consistent with first-order rather than the
expected second-order kinetics.
In order to gain a better understanding of the alkylation we
undertook a kinetic and mechanistic study of the reaction. As it
was already known that deprotonation of 2 was required for
the reaction to proceed we also investigated this in isolation
from the alkylation. The results of these studies showed the
active alkylating agent to be the Azetidinium ion, 4, which was
formed reversibly from 3 (Scheme 2). Under most conditions
this was found to be the rate-limiting process in the alkylation
reaction. The deprotonation of 2 by K2CO3 was found to be
rapid relative to the overall reaction time. The base
stoichiometry of 0.8 equiv, which had been selected based
RESULTS AND DISCUSSION
■
Preliminary Kinetic Studies. The simple alkylation of 2
to form cediranib, 1 (Scheme 1), would be expected to show
second-order kinetics with a kinetic dependence upon the
concentrations of both reactants. However, it was found that
reactions carried out with initial reactant concentrations
varying between 0.066 and 0.231 M occurred on very similar
time scales (Figure 1). These reaction progress curves give a
reasonable fit to first-order kinetics over most of the reaction.
Additionally, little change was observed in the rate of reaction
if indolphenol, 2, was ionized, by stirring it for a period with
K2CO3, prior to the addition of a solution of 3 in methyl
tertiary butyl ether (MTBE) or if 3 was charged immediately
after the K2CO3. These observations are inconsistent with a
direct nucleophilic substitution between the anion of 2 and 3,
which would be expected to exhibit a kinetic dependence upon
both reactant concentrations.
Qualitatively, these observations are consistent with the
reactions shown in Scheme 3, in which product formation
Special Issue: Excellence in Industrial Organic Synthesis 2019
Received: September 24, 2018
Published: November 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02458
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Scheme 1. Alkylation To Form Cediranib, 1
At high [2], k2[2] ≫ k′−1 and eq 1 simplifies to simple first-
order kinetics, while, at low [2], k′−1 ≫ k2[2] meaning that eq
1 simplifies to second-order kinetics. Simultaneous fitting of
the rate of loss of indolphenol, 2, data to eq 1 (Figure 2) gave
Scheme 2. Formation of Azetidinium Ion, 4
Figure 2. Best-fit curves for the fitting of eq 1 to the Indolphenol, 2,
loss curves generated at 80 °C in 10:1 NMP/MTBE with 1.05 equiv
of 3. k1 = 5.6 × 10−4 s−1 and k′−1/k2 = 0.034 M.
Figure 1. Reaction progress graphs for the alkylation of 2 by 1.05
equiv of 3 in 10:1 NMP/MTBE at 80 °C at different concentrations
of 2.
values of k1 of 5.6 0.3 × 10−4 s−1 and k′−1/k2 0.034 0.006
M.12 The good agreement obtained between the model and
the data provides strong support for the proposed mechanism
(Scheme 3) involving reaction via the azetidinium ion, 4. The
value of 0.034 M obtained for k′−1/k2 represents the
concentration of 2 at which the reaction changes from being
predominantly first-order to being predominantly second-
order. At high concentrations the rate-limiting step in the
reaction is therefore the intramolecular cyclization of 3 to form
the azetidinium ion, 4.
Scheme 3. Proposed Reaction Scheme for the Alkylation of
Indolphenol, 2, by Azetidinium Ion, 4, Formed via the
Cyclization of Chloropyrrolidine, 3
In order to provide additional support to the proposed
mechanism, the rates of formation and reaction of the
azetidinium ion, 4, were studied further in isolation from
each other.
Deprotonation of Indolphenol. The use of K2CO3 as a
heterogeneous base in the alkylation reaction to form 1 adds
an additional complication, as indolphenol, 2, deprotonation is
required for reaction to occur. This raises the possibility that
the rate of the deprotonation could control the rate of the
alkylation reaction (Scheme 4). Studies of the deprotonation
of 2-cyanophenol by K2CO3 in 1,1-dimethylformamide (DMF)
have demonstrated that a similar heterogeneous deprotonation
reaction is not instantaneous.13
results from the alkylation of Indolphenol, 2, by the
azetidinium ion, 4, formed by the slow, intramolecular
cyclization of chloropyrrolidine, 3.6,7 Azetidinium ions, which
are generally prepared by the alkylation of azetidines, are
known to be effective alkylating agents.8−11 This hypothesis
was tested in our investigations of the alkylation reaction.
Treating the azetidinium ion, 4, as a reactive intermediate
and applying the steady-state approximation gives the below
rate law (eq 1) for the formation of 1 and consumption of 2. In
deriving eq 1, it was assumed that [Cl−] is almost constant and
it is included in k′−1 (k′−1 = k−1[Cl−]). This is due to the
reaction generating KCl and KHCO3 as stoichiometric
byproducts, which precipitate from the reaction solvent.
An in situ attenuated total reflectance (ATR) UV−vis
spectroscopic study of the deprotonation of 2 by K2CO3 at 80
°C in NMP was therefore undertaken. It was found that 2
could be observed at 325 nm, while the UV absorbance due to
k1k2[3][2]
k−1 + k2[2]
d[1]
dt
d[2]
dt
= −
=
′
(1)
B
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Article
produced as a byproduct of the deprotonation by KHCO3.
This experiment gave a similar initially rapid deprotonation to
the static head experiment, consistent with this portion of the
curve being due to K2CO3. The subsequent KHCO3 mediated
phase of the deprotonation showed a significant acceleration
consistent with the hypothesis that the removal of CO2 from
the deprotonation would promote the KHCO3 mediated
reaction. Further support was provided to this hypothesis by
the performance of the deprotonation reaction when carried
out under an atmosphere of CO2. In this case the initial rapid
K2CO3 mediated reaction gave a lower level of deprotonation
than had been seen previously, followed by a very slow rate of
ongoing deprotonation. The reduction in the initial anion yield
was postulated to be due to CO2 combining with water present
in the NMP to generate a small quantity of carbonic acid,
which partially neutralized the K2CO3 charged to the
experiment. The addition of water (3.5% w/w) had an adverse
effect upon the deprotonation of 2 and therefore the progress
of the alkylation reaction, consistent with experimental
observations during our development work.
Scheme 4. Scheme for the Formation of Cediranib, 1,
Including the Deprotonation of Indolphenol, 2 (ArOH),
and Related Phase Equilibria
Taken together the results of this study suggest that the
likely explanation for the extension in the time taken to reach
95% conversion observed when scaling up the alkylation
reaction was due to the substoichiometric K2CO3 charge. In
the laboratory the loss of CO2 from the reaction means that
using KHCO3 to complete the reaction is not problematic,
whereas the operation of the reaction under a static head of
nitrogen in a pilot plant slowed CO2 disengagement leading to
a long reaction tail. Operation of the reaction under a nitrogen
sweep was therefore trialled in the laboratory and was
demonstrated to be capable of achieving an acceptable reaction
conversion with 0.6 equiv of K2CO3. This option was not
pursued further, as it led to elevated levels of over-reaction
products being formed.
the phenoxide anion showed the expected bathochromic shift
with absorptions at 270 and 353 nm.14 As 2 had no absorbance
at 353 nm this wavelength was used to monitor the
deprotonation. A crude calibration curve of absorbance versus
the solution concentration of the phenoxide was generated by
adding known aliquots of potassium hydride to a solution of 2
in NMP.15 Using this practical extinction coefficient it was
possible to profile the deprotonation of 2 by K2CO3 at 80 °C
under a range of process relevant conditions (Figure 3).
Formation and Reaction of Azetidinium Ion, 4. Initial
attempts to study the formation of 4 by heating a solution of
chloropyrrolidine, 3, in the reaction solvent (10:1 NMP/
1
MTBE) gave little reaction by H NMR. However, further
NMR experiments demonstrated that 3 reacted in D2O to give
a single species, which was identified as the azetidinium ion, 4.
It was not possible to isolate 4, prepared by stirring a
suspension of 3 in water, as its chloride salt. Addition of either
potassium tetraphenylborate or potassium hexafluorophos-
phate to this solution did give rise to isolable crystalline solids,
which could be recrystallized from acetonitrile. The
tetraphenylborate salt of 4 proved to be soluble in NMP and
was used to study the kinetics of its reaction with indolphenol,
2 (see below).
(i) Kinetics of Azetidinium Ion, 4, Formation. The failure of
the synthetic experiments to stoichiometrically generate 4 in
the reaction solvent led us to hypothesize that the high activity
of chloride in an aprotic solvent mixture suppressed the
formation of 4. Such reversibility in the formation of
azetidinium ions has been observed in studies involving the
cyclization of substituted 3-chloropropyl systems.6 In the
synthesis of cediranib, 1, this is overcome by the presence of a
high solution concentration of potassium in the form of the
potassium salt of indolphenol, 2, which removes the chloride
from solution as KCl, leaving 4 in solution as its
indolphenolate salt (Scheme 5). Addition of a soluble
potassium salt, potassium tetraphenylborate, to a solution of
chloropyrrolidine, 3, in the reaction solvent, led to the
Figure 3. Deprotonation curves for 2 with 0.85 equiv of K2CO3 in
NMP at 80 °C: effect of processing conditions.
Profiling the deprotonation of 2 under a static head of
nitrogen provided a reasonable mimic of the manner in which
the formation of 1 had been operated at scale. This experiment
showed an initial rapid phase followed by a slower second
phase (Figure 3) and achieved 90% deprotonation after 4 h.
The initial rapid deprotonation was believed to be due to the
K2CO3 present initially deprotonating 2, while the subsequent
slower deprotonation was believed to be due to KHCO3 acting
as a base to complete the deprotonation in agreement with the
findings of Forryan et al.13 The impact of using a sweep of
nitrogen through the headspace of the deprotonation reaction
was therefore investigated as a means of removing the CO2
C
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Article
Scheme 5. Scheme Illustrating the Coupling of the
Precipitation of KCl with the Formation of Azetidinium
Ion, 4, and Cediranib, 1
precipitation of KCl as the chloride as it was formed and made
it possible to drive the reaction to completion.
Figure 4. Best-fit plot for the cyclization of 3 (0.26 M) in 10:1 NMP/
d3-MTBE at 70 °C. The best-fit lines were calculated using eqs 2−4
with k1 = 1.48 × 10−4 s−1, k′−1 = 8 × 10−6 s−1, and k3 = 1.96 × 10−4
M−1 s−1.
This allowed us to undertake an in situ 1H NMR study of the
kinetics of the formation of 4 in 10:1 NMP/d3-MTBE at 60,
70, and 77 °C. In addition to being able to see the loss of 3 and
formation of 4, we could also observe the slow formation of an
additional species, which appeared to form from 4. This was
isolated as its tetraphenylborate salt and shown to be the
chloropyrrolidine dimer, 5 (Scheme 6). The formation of the
Table 1. Rate Constants for the Formation of Azetidinium
Ion, 4, in 10:1 NMP/d3-MTBE
a
ab
,
a
temp (°C)
104 k1 (s−1
)
104 k′−1 (s−1
)
104 k3 (M−1 s−1
)
60
70
77
0.56 0.02
1.48 0.09
2.27 0.11
0.03 0.02
0.08 0.07
0.13
0.84 0.07
1.96 0.34
3.70 0.41
Scheme 6. Kinetic and Mechanistic Scheme for the
Formation of Azetidinium Ion, 4, and Dimer, 5, from
Chloropyrrolidine, 3 (Including the H NMR Resonances
c
1
a
Used for Reaction Monitoring)
The uncertainties quoted for k1, k′−1, and k3 are the 95% confidence
b
limits derived from the fitting. The reverse rate constant, k′−1, was
found to be strongly correlated with the other parameters in the
model, as should be expected, and the confidence in the fitted values
c
is therefore very low. The uncertainty in the fitted value of k′−1 is
greater than the fitted value meaning that the value is not statistically
significant.
d[4]
′
= k1[3] − k−1[4] − k3[3][4]
(3)
(4)
dt
d[5]
dt
= k3[3][4]
where k’−1=k−1[Cl−]
1
dimer, 5, complicated the analysis of the H NMR based
The temperature dependence of the cyclization, k1, and
dimerization, k3, rate constants follow the Arrhenius equation
(Figure 5). The resultant activation energies are tabulated
(Table 2) for each reaction alongside the enthalpy and entropy
of activation obtained from Eyring plots.21 The large negative
entropy of activation obtained for the cyclization of 3 to yield 4
is rather surprising for a cyclization reaction to yield a small
ring.22 This is especially so when compared to the activation
entropy of the bimolecular reaction to yield 5, which is similar.
A potential explanation may be found in the poor solvation of
anions by dipolar aprotic solvents such as NMP, for which the
free energy of transfer for chloride from water into NMP is
55.2 kJ mol−1 at 25 °C.23 It is therefore plausible that the
liberated chloride will either be associated with the product
cation or stabilized by an interaction with another cation
present in the reaction. Such associative interactions could
offset the entropic gain to be expected from a unimolecular
reaction that generates two product ions, leading to the
unexpectedly large negative entropy of activation.
kinetic data because its CH2Cl resonance partially overlapped
the CH2Cl resonance of chloropyrrolidine, 3. The application
of mixed Gauss−Lorenz fitting16 made it possible to
deconvolute the overlapping triplets17 and facilitated the
generation of concentration versus time profiles (Figure 4)
for the cyclization of 3. The formation of the dimer, 5, was not
observed under normal preparative conditions due to the rapid
reaction of 4 with 2 (see below).
The NMR derived concentration profiles were fitted12 to a
model (eqs 2−4) based on Scheme 6 to give the tabulated
(Table 1) best-fit values of the rate constants.18 A typical best-
fit plot is shown in Figure 4.19 In formulating eqs 2−4 it was
assumed that the Cl− concentration is held constant at the
solubility of KCl.20 A simple irreversible model, without the
k′−1 term, was also investigated and found to give a worse fit to
the data.
d[3]
′
= −k1[3] + k−1[4] − k3[3][4]
(2)
dt
D
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Figure 6. Reaction of indolphenol, 2, with either 3 or 4 to form
cediranib, 1, in 10:1 NMP/MTBE at 70 °C. Chloropyrrolidine, 3,
reaction (circles): [2] = 0.233 M, [3] = 0.252 M. Azetidinium
tetraphenylborate, 4, reaction (triangles): [2] = 0.193 M, [4] = 0.197
M.
Figure 5. Arrhenius plot for the cyclization of 3 and its reaction with
4.
A comparison of the first-order rate constant for the
consumption of 3 in its reaction with 2, 5.6 × 10−4 s−1 at 80
°C, with the predicted rate constant for the formation of 4
from 3 of 3.0 × 10−4 s−1 shows them to be similar. This is
consistent with the proposed mechanistic hypothesis that the
cyclization of 3 to generate 4 is the rate-limiting step in the
formation of 1 at high concentrations (>0.04 M), which
suggests that they should be comparable.
(ii) Kinetics of the Reaction between Indolphenol, 2, and
Azetidinium Ion, 4. A comparison of the reaction between the
azetidinium ion, 4, as its tetraphenylborate salt and
chloropyrrolidine, 3, with indolphenol, 2, potassium salt
under similar conditions is shown (Figure 6). As expected,
the reaction between the azetidinium ion, 4, and 2 is rapid,
achieving 50% conversion in less than 4 min, while the reaction
with 3 is significantly slower, taking almost 100 min to reach
the same point. This is consistent with the mechanistic
hypothesis that the formation of 4 from 3 is the rate-limiting
step in the formation of 1.
Neither of the reactions (Figure 6) gave complete
conversion of 3 or 4 to 1 due to the presence of a significant
side reaction, which forms an isomeric byproduct. Comparison
of the shapes of the profiles for the formation of 1 and the
isomeric, N-alkylated, byproduct (Figure 7) from a reaction of
4 with 2 shows them to be similar, suggesting that the products
are formed via competitive reactions with the same form of
rate law (Scheme 7). Fitting of reaction profile data for the
reaction of 4 as its tetraphenylborate salt with the potassium
salt of 2 to a competitive second-order model (eqs 5−7) based
on this hypothesis provides a good fit to the experimental data
(Figure 8). The isomer is a result of the indolphenol, 2, being
an ambident nucleophile and capable of reacting via nitrogen
as well as oxygen. No evidence was found for the opening of
the pyrrolidine ring of the azetidinium ion, 4, which is
consistent with the 25 000-fold difference in reactivity between
Figure 7. Comparison of the profiles for the formation of cediranib, 1,
and the isomeric byproduct in the reaction of the azetidinium ion, 4,
0.18 M and indolphenol, 2, potassium salt 0.19 M in 10:1 NMP/
MTBE at 70 °C.
Scheme 7. Kinetic Scheme for the Formation of Cediranib,
1, and the Isomeric Byproduct from the Reaction of the
Azetidinium Ion, 4, and Indolphenol, 2, Potassium Salt
the 1,1-dimethyl azetidinium ion, 6, and its pyrrolidinium
analogue, 7.10
The isomer formation is a known side reaction in the
synthesis of cediranib, 1, and represents a yield loss rather than
a quality issue, as the isomer is purged in the crystallization of
a
Table 2. Summary of Activation Parameters for the Cyclization of 3 and Formation of 5
reaction
constant
Ea (kJ mol−1
)
A
ΔH‡ (kJ mol−1
)
ΔS‡ (J K−1 mol−1
)
cyclization of 3
dimerization
k1 (s−1
)
80 15
2.5 × 108
1.3 × 109
78 15
−94 44
−80 15
k3 (M−1 s−1
)
84
5
81
5
a
The uncertainties quoted are the 68% confidence bands from a simple linear regression analysis to determine the best-fit line.
E
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5) and the rate-limiting step is the formation of the
azetidinium ion, 4.
Comparing the rate constant for the formation of dimer 5 at
70 °C (2.29 × 10−4 M−1 s−1) with the rate constant for the
reaction of azetidinium ion 4 with the potassium salt of
indolphenol, 2 (2.4 × 10−2 M−1 s−1), shows that product
formation should outcompete dimer formation. However, this
will not be the case if the deprotonation of indolphenol, 2, is
inefficient. This may in part explain the slow reaction observed
when the process was scaled-up.
In summary, the first-order kinetics observed during
investigations of the alkylation of a phenoxide by an alkyl
chloride to synthesize cediranib have been rationalized in
terms of the alkyl chloride undergoing a slow intramolecular
cyclization reaction to generate an azetidinium ion, which is
the active alkylating species in the etherification. The kinetics
of the cyclization of the alkyl chloride were studied
1
independently by H NMR spectroscopy and shown to be
Figure 8. Best fit curves for the reaction of 4 BPh4− (0.18 M) with 2
K+ (0.19 M) in 10:1 NMP/MTBE at 70 °C. The best-fit lines were
calculated using eqs 5−7 with k2 = 2.40 × 10−2 M−1 s−1 and k4 = 2.29
× 10−3 M−1 s−1.
consistent with this hypothesis. Our isolation of the
azetidinium ion as its tetraphenylborate salt enabled us to
demonstrate that the azetidinium ion reacts rapidly with the
phenoxide in a reaction that exhibited second-order kinetics,
which agrees with our mechanistic proposal. Additional studies
of the heterogeneous deprotonation of the phenol by K2CO3
confirmed that significant deprotonation occurs relatively
rapidly under the synthetic conditions. However, the process
uses substoichiometric K2CO3, which means that a portion of
the deprotonation is carried out by KHCO3, and therefore
generates CO2 as a byproduct. Failure to disengage this CO2
from the reaction mass has been demonstrated to be capable of
stalling the deprotonation. It is also a potential cause of the
extended reaction times observed at plant scale when the
process was scaled-up. This was mitigated by increasing the
K2CO3 charge used in the process, so that the deprotonation
by KHCO3 was a less significant contributor to the progress of
the reaction. In the event of the deprotonation reaction
stalling, the azetidinium ion will continue to be generated
whereupon it has the potential to dimerize or react through
other manifolds.
cediranib, 1. The competitive nature of the isomer formation
means that changes to the reaction stoichiometry, order, or
mode of reactant addition will not modify the selectivity of the
reaction for 1 over its isomer.
d[4]
dt
d[2]
dt
−
= −
= k2[2][4] + k4[2][4]
(5)
(6)
(7)
d[1]
dt
= k2[2][4]
d[Isomer]
dt
= k4[2][4]
Attempts to simultaneously fit reaction progress data from
reactions at two different process concentrations to a model
based on eqs 5−7 failed. Individual fitting of both sets of
experimental data was successful to give the tabulated best-fit
rate constants (Table 3).12,24 These clearly show the reaction
EXPERIMENTAL SECTION
■
Table 3. Concentration Dependence of Rate Constants for
the Formation of Cediranib, 1, from Azetidinium, 2,
Tetraphenylborate and Indolphenol, 2, Potassium Salt in
10:1 NMP/MTBE at 70 °C
General Information. Except where stated, all reagents were
purchased from commercial sources and used without further
purification. Unless stated to the contrary, reactions were heated by
means of circulating oil baths operating in batch temperature mode.
1H NMR and 13C NMR spectra were recorded on a Bruker DRX
spectrometer operating at 499.9 and 125.7 MHz or on a Bruker DPX
spectrometer operating at 400 and 101 MHz respectively. All spectral
data were collected at 300 K unless it is stated to the contrary.
Chemical shifts (δ) are quoted in parts per million (ppm) relative to
TMS. Coupling constants (J) are reported in hertz (Hz) to the
nearest 0.1 Hz. The multiplicity abbreviations used are s, singlet; d,
doublet; and m, multiplet. Signal assignments were achieved by
analysis of HSQC-DEPT, COSY, and HMBC experiments. Mass
spectra (high resolution) were obtained using electrospray ionization
in positive ion mode (ESI) on a Bruker Daltonics MicrO-TOFQ
spectrometer. Strengths quoted for materials were determined by
HPLC against an external standard of the appropriate compound or
[2K] (M)
[4BPh4] (M)
102 k2 (M−1 s−1
)
102 k4 (M−1 s−1
)
0.193
0.103
0.183
0.101
2.40 0.12
6.10 0.13
0.23 0.02
0.33 0.02
to be significantly faster under more dilute conditions. A likely
explanation of this behavior is that strong ion pairing is
occurring between the anion of indolphenol, 2, and K+ as has
been observed previously in kinetic studies of a range of
phenoxide ions with butyl bromide in the presence of alkali
metal cations.25 The formation of an ion pair leads to a portion
of the phenoxide being in a less reactive or unreactive complex
and therefore reduces the rate of reaction as the concentration
of the metal cation is increased. This behavior was not
investigated further, as it was of limited relevance to the
conditions used to form cediranib, 1, where the K+
concentration is kept low by the precipitation of KCl (Scheme
1
by H NMR, at least in duplicate, against an internal standard of
benzyl benzoate. HPLC analyses were undertaken using the below
method on an Agilent 1100 series instrument with a quaternary pump
and variable wavelength diode detector.26
Sample Kinetic Procedures. Preliminary Kinetic Studies.
Indolphenol, 2, NMP solvate (19.42 g @99.8% w/w, 44.3 mmol),
and K2CO3 (6.9 g, 35.4 mmol) were charged to a 250 mL jacketed
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Article
reactor fitted with a retreat curve agitator, thermocouple, condenser,
and N2 bubbler. NMP (152 mL) was charged, and the agitator was
started (250 rpm). The slurry was heated to 80 °C and then held at
80 °C for 1 h before chloropyrrolidine, 3, in MTBE (15.75 g @ 43.6%
w/w, 46.5 mmol) was added and rinsed in with MTBE (3.6 mL). The
reaction mass was stirred at 80 °C for 4 h sampling periodically.
Sample preparation procedure: 30−40 μL of reaction mass added into
25 mL volumetric flask and make up to the line with HPLC sample
diluent.
carry out the hydrogenation on a scale that meant it could be used to
supply a number of alkylation reactions.
A solution of indolphenol, 2, in NMP (400 g @ 10% w/w, 0.118
mol) was charged to a 1 L jacketed vessel fitted with a retreat curve
agitator, thermocouple, condenser, and N2 bubbler. Agitation was
started (350 rpm), and the contents of the vessel were thermostated
to 20 °C. Acetonitrile (400 mL) was charged over 30 min via a
pressure equalizing dropping funnel, and the solution stirred at 20 °C
for 4 h (seed may optionally be added after the acetonitrile). The
resultant pale buff slurry was heated to 46 °C over 30 min, held at 46
°C for a further 30 min, cooled to 0 °C over 4 h, and finally cooled to
−20 °C over 3 h. The solid product was isolated on a split Buchner
funnel under reduced pressure after stirring for 1 h at −20 °C. An
acetonitrile displacement wash (80 mL) was applied to the filter cake,
and the damp product was dried overnight in a vacuum oven at 45 °C
to give indolphenol 2 NMP solvate (36.39 g @ 99.8% w/w, 70%
yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 11.11 (br
s, 1H), 10.38 (br s, 1H), 8.41 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H),
7.19−7.09 (m, 1H), 7.01−6.90 (m, 1H), 6.26−6.18 (m, 1H), 4.00 (s,
3H), 2.41 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ = 164.4,
154.2, 151.8, 149.6, 148.6, 145.5 (d, J = 245.3 Hz), 137.1, 136.0 (d, J
= 10.9 Hz), 130.6 (d, J = 11.3 Hz), 117.7 (d, J = 19.2 Hz), 115.3,
109.6, 108.6, 106.26 (d, J = 3.4 Hz), 101.2, 94.8, 55.8, 12.8; HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C18H15FN3O3 340.1092;
found 340.1094.
1
Chloropyrrolidine Cyclization Kinetics by H NMR. KBPh4 (391
mg @ 97% w/w, 1.06 mmol) was dissolved in NMP (2.17 mL).
Chloropyrrolidine, 3, (105 mg, 0.71 mmol), which had been
evaporated to an oil at room temperature, was dissolved in d3-
MTBE (210 μL). The two solutions were mixed thoroughly and
transferred to a 5 mm NMR tube. The tube was placed in a 400 MHz
NMR spectrometer operating at a probe temperature of 350 K, and
1H NMR spectra were recorded periodically for 7 h. A blank sample
without the chloropyrrolidine was used to check the relaxation times
to ensure that the delay between pulses was sufficient.
Kinetics of Azetidinium, 4, Tetraphenylborate with Indolphenol,
2, Potassium Salt. Indolphenol, 2 (4.13 g at 72.6%, 7.95 mmol),
potassium salt was charged to a dry 80 mL multinecked jacketed
vessel containing a magnetic stirrer flea followed by NMP (29.9 mL).
The slurry was heated to 70 °C with stirring under N2 to give a clear
red solution. Azetidinium tetraphenylborate, 4 (3.58 g @ 97.2% w/w,
8.06 mmol), was charged and rinsed in with MTBE (3.0 mL), and the
reaction mass was stirred at 70 °C for 6 h with periodic sampling.
Sample preparation procedure: 40 μL of reaction mass added into a
25 mL volumetric flask and make up to the line with HPLC sample
diluent.
Sample Indolphenol Deprotonation Procedure. A 500 mL
jacketed reactor was set up with a retreat curve agitator,
thermocouple, condenser, and N2 bubbler. A 12.7 mm titanium
ATR-UV vis probe with a sapphire ATR crystal was positioned in the
vessel above the agitator. The probe was connected to a Zeiss UV−
visible spectrometer (running Aspect Plus V1.52) via 3 m fiber optic
cables. NMP (150 mL) was charged to the vessel and heated to 80 °C
with stirring. Once the temperature was stable, an NMP background
spectrum was recorded. Indolphenol, 2 (9.7 g @ 99% w/w, 22.2
mmol), NMP solvate was charged and washed with NMP (10 mL)
and the mixture was stirred at 80 °C for 10 min. Data collection was
started, collecting spectra from 245 to 510 nm every minute for the
first hour and then every 2 min for the next 2 h. After 10 min, K2CO3
(2.6 g, 18.8 mmol) was charged and the reaction was stirred for 3 h
under a static head of N2.
Synthetic Procedures. Indolphenol, 4-[(4-Fluoro-2-methyl-1H-
indol-5-yl)oxy]-6-methoxyquinazolin-7-ol, 2 as Its NMP Solvate.
3% Palladium on carbon (1.0 g of 60% water wet catalyst, 0.17 mmol
Pd) was charged to a 1 L jacketed hydrogenation vessel fitted with a
six blade Rushton turbine agitator, and the vessel was purged three
times with N2. 7-(Benzyloxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquinazoline3 (76.1 g @ 98.6% w/w, 0.175 mol) was
dissolved in 1-methyl-2-pyrrolidinone, NMP (407 mL), and the
solution was transferred into the hydrogenator followed by NMP (38
mL) as a wash. The hydrogenator was purged three times with N2.
The contents of the hydrogenator were heated to 45 °C with stirring.
Once the temperature was stable at 45 °C, the agitator was stopped,
and the vessel was purged 3 times with hydrogen before pressurizing
to 3 barg with hydrogen. Agitation was restarted, the vessel contents
were maintained at 45 °C, and the hydrogen uptake was monitored at
constant pressure. After 3 h, the hydrogen uptake had leveled off at
4.14 L (97% of theory). The hydrogen delivery and agitator were
stopped, and the vessel was purged three times with N2. The batch
was discharged from the vessel and filtered through a double layer of
Pall filter paper to remove the catalyst, and the vessel was rinsed with
NMP (60 mL). These rinsings were used to wash the catalyst and
combined with the product solution. A brown solution of 2 in NMP
(564 g @ 10% w/w, 96% yield) was obtained.
Chloropyrrolidine, 1-(3-chloropropyl)pyrrolidine,27 3, as a solution
in MTBE. Chloro-pyrrolidine, 3, oxalate (58.1 g, 0.244 mol) and
deionized water (100 mL) were charged to a 500 mL jacketed
reaction vessel fitted with a retreat curve agitator, pressure equalizing
dropping funnel, thermocouple, condenser, and N2 bubbler. The
mixture was agitated (600 rpm), and methyl tert-butyl ether (MTBE)
(50 mL) was charged. The resultant biphasic solution was cooled to
10 °C, and 50% w/w KOH solution (60.8 g, 0.531 mol) was added
over 1 h keeping the temperature below 20 °C. After the mixture was
warmed to 20 °C, the agitator was stopped, and the phases were
separated. The lower pale yellow aqueous phase was returned to the
vessel, MTBE (50 mL) was added, and the mixture was agitated for
15 min at 20 °C. The agitator was stopped, the phases were separated,
and the combined organic phases (∼130 mL) were returned to the
vessel. A 30% w/w solution of KCl (25 mL) was charged, and the
mixture was agitated for 30 min at 20 °C. The phases were allowed to
separate, and the upper phase was retained. This gave chloropyrro-
lidine, 3 (108 g @ 33% w/w, 0.241 mol), as a solution in MTBE.
Free basing of 3 was usually carried out on a scale sufficient to
supply a number of experiments, and the resulting solution of 3 in
MTBE was stored in the freezer. We also used a similar procedure
with less base to free base the HCl salt of 3.
AZD2171, Cediranib, 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-
6-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]quinazoline, 1. K2CO3
(2.6 g, 18.6 mmol) was charged to a 250 mL jacketed reaction
vessel fitted with a retreat curve agitator, thermocouple, condenser,
and N2 bubbler. The vessel was thoroughly purged with N2, and
indolphenol, 1 (78.9 g @ 10% w/w, 23.2 mmol), in NMP was
charged followed by an NMP (7.9 mL) wash. Chloropyrrolidine, 3
(10.9 g @ 33% w/w, 24.4 mmol), in MTBE was charged followed by
MTBE (1 mL) as a wash. The agitator was started (300 rpm), the
vessel was heated to 72 °C over 30 min, and the contents stirred at 72
°C under N2 for 21 h. Water (87 mL) was charged maintaining the
temperature above 60 °C, and the slurry was allowed to self-cool to
ambient with stirring. The solid product was isolated by filtration
under reduced pressure after 2 h, and the filter cake was washed with a
mixture of NMP (7.2 mL) and water (7.2 mL) followed by three
water washes (14.4 mL each). The product was dried in a vacuum
oven to give cediranib, 1 (9.07 g @ 99.5% w/w, 86% yield), a white
solid; 1H NMR (400 MHz, DMSO-d6) δ = 11.32 (br s, 1H), 8.49 (s,
1H), 7.59 (s, 1H), 7.36 (s, 1H), 7.15 (dd, J = 8.5, 0.4 Hz, 1H), 6.98
(dd, J = 8.5, 7.4 Hz, 1H), 6.24−6.21 (m, 1H), 4.23 (t, J = 6.5 Hz,
2H), 3.98 (s, 3H), 2.55 (t, J = 7.2 Hz, 2H), 2.47−2.42 (m, 4H),
2.42−2.38 (m, 3H), 2.03−1.92 (m, 2H), 1.72−1.64 (m, 4H);
13C{1H} NMR (101 MHz, DMSO-d6) δ = 164.6, 155.1, 152.3, 150.2,
At plant scale this solution was telescoped directly into the
alkylation reaction to form 1. In the laboratory it was customary to
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The Journal of Organic Chemistry
Article
148.8, 145.7 (d, J = 245.4 Hz, 1C), 137.5, 136.3 (d, J = 11.3 Hz, 1C),
130.7 (d, J = 11.3 Hz, 1C), 117.9 (d, J = 18.8 Hz, 1C), 115.5, 109.2,
107.3, 106.7 (d, J = 3.4 Hz, 1C), 100.7, 95.1, 67.1, 56.0, 53.6 (s, 2C),
52.1, 27.9, 23.1 (s, 2C), 13.3; HRMS (ESI/Q-TOF) m/z: [M + H]+
calcd for C25H28FN4O3 451.2140; found 451.2131.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ian.ashworth@astrazeneca.com.
ORCID
Azetidinium Ion, 4-Azoniaspiro[3.4]octane Tetraphenylborate,
4. Chloropyrrolidine, 3 (20 g, 0.135 mol), in toluene (200 mL) was
charged to a 500 mL jacketed reaction vessel fitted with a retreat
curve agitator, thermocouple, condenser, and N2 bubbler and heated
at 80 °C for 3 h. Water (25 mL) was added to the mixture over 30
min keeping the reaction temperature between 70 and 85 °C. The
mixture was then allowed to settle for 15 min, and the lower aqueous
phase separated off. The organic phase was washed with water (25
mL) at 80 °C, and the lower aqueous phases were combined. The
aqueous solution (containing the azetidinium chloride salt) was then
added to a solution of sodium tetraphenylborate (46.6 g @ 99.5%w/
w, 0.135 mol) in acetone (180 mL) over 15 min at 20 °C. The white
precipitate was filtered, washed with water (3 × 100 mL), and then
dried in a vacuum oven at 45 °C for 48 h to give azetidinium
tetraphenylborate, 4 (52.4 g @ 97% w/w, 87% yield), a white
crystalline solid; mp 233−234 °C; 1H NMR (400 MHz, DMSO-d6) δ
= 7.32−7.06 (m, 8H), 7.04−6.86 (m, 8H), 6.86−6.68 (m, 4H), 4.34−
4.04 (m, 4H), 3.58−3.42 (m, 4H), 2.46−2.33 (m, 2H), 2.01−1.80
(m, 4H); 13C{1H} NMR (101 MHz, DMSO-d6) δ = 164.1−162.5
(m, 4C), 135.6−135.3 (m, 8C), 125.4−125.1 (m, 8C), 121.5 (s, 4C),
62.1−61.9 (m, 4C), 20.7 (s, 2C), 14.1; HRMS (ESI/Q-TOF) m/z:
[M]+ calcd for C7H14N 112.1121; found 112.1128.
Ian W. Ashworth: 0000-0001-7210-3875
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Firstly, the authors would like to acknowledge the significant
intellectual and experimental contribution made to this work
by Dr. E. A. Arnott. The authors also thank Dr. S. Coombes
and Dr. A. Bristow for assistance with NMR and mass
spectrometric characterization, respectively. Mrs. E. Brazier,
Mr. M. Senior, and Mr. M. Evans provided materials to
support this work, whilst Dr. M. F. Jones provided significant
encouragement and support. Finally, the authors acknowledge
the support of AstraZeneca in carrying out this work.
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2C), 59.5−59.4 (m, 1C), 58.3−58.1 (m, 1C), 54.8 (s, 2C), 53.1, 42.5,
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ASSOCIATED CONTENT
■
S
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02458.
Repetitive scanning UV−vis plot of the deprotonation of
2; plot of absorbance at 353 nm versus phenoxide
concentration for the deprotonation of 2; best-fit plots
for the cyclization of 3 at 60 and 77 °C; Micromath
Scientist models and notes on the kinetic fitting;
extension to eqs 2−4 to include the equilibrium
solubility of KCl; Eyring plots for the cyclization of 3
(k1) and its reaction with 4 (k3); best-fit plot for the
reaction of 4 (0.10 M) with the potassium salt of 2 (0.10
M) at 70 °C; HPLC method for cediranib 1 and
indolphenol 2; 1H and 13C NMR spectra of cediranib, 1,
indolphenol (NMP solvate), 2, azetidinium tetraphe-
nylborate, 4, and dimer tetraphenylborate, 5 (PDF)
(12) Fitted using Micromath Scientist V3, www.micromath.com.
The quoted errors are the 95% confidence intervals arising from the
fitting. A copy of the model used in text format may be found in the
Supporting Information (SI).
H
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(14) A repetitive scan plot of the spectra during the deprotonation
reaction may be found in SI Figure S1.
(15) A plot of absorbance at 353 nm versus potassium
indolphenolate, 2, concentration may be found in SI Figure S2.
(16) Using the peak fitting algorithm within ACD/Spectrus
Processor, Advanced Chemistry Development Inc., Toronto, Canada,
www.acdlabs.com.
(17) While the −CH2Cl resonances of 3 and 5 are triplets, the N+−
CH2− signals of 4 are a pseudotriplet due to nonequivalence of the
protons on the adjacent CH2 group.
(18) The correlation between the rate constants observed in fitting
the model is a mathematical consequence of fitting all the constants in
the model. This issue was avoided when fitting eq 1 by fitting the ratio
k′−1/k2 rather than k′−1 and k2. However, in this case we were
interested in obtaining an estimate of the rate constant of the
dimerization reaction from the limited data available. An independent
measurement of the equilibrium constant (K = k1/k′−1) for the
cyclization of 3 would resolve the issue, as would simultaneous fitting
of multiple sets of profile data collected at different reactant
concentrations.
(19) Best-fit plots for the reaction at 60 and 77 °C may be found in
SI Figures S3 and S4, respectively.
(20) This is a simplification that ignores the fact that KCl has a
solubility product, Ks = [K+][Cl−]. A correct treatment may be found
in the SI. This was unsuitable for application with the available
experimental data, as it introduced an extra parameter to be fitted in a
model that was already exhibiting significant correlation between the
parameters in the fitting.
(21) An Eyring plot for both k1 and k3 may be found in SI Figure S5.
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bifunctional chain molecules’. Acc. Chem. Res. 1981, 14, 95−102.
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in 10:1 NMP/MTBE at 70 °C may be found in SI Figure S6.
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influence on the rate of formation of benzo-18-crown-6 and of other
Williamson-type reactions’. J. Am. Chem. Soc. 1983, 105, 555−563.
(26) Full details of the HPLC method used and typical retention
times may be found in the SI.
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I
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