Flexible and scalable route to HDAc inhibitors containing an unusual trisubstituted pyridine core

Article abstract of DOI:10.1021/op300021m

A scalable route to histone deacetylase inhibitors containing an unusual 2-aryl-3-cyano-5-aminomethylpyridine core has been developed which has the flexibility to deliver a range of compounds on at least a multigram scale. The key step involves a novel Ma

Full text of DOI:10.1021/op300021m

Article
pubs.acs.org/OPRD
Flexible and Scalable Route to HDAc Inhibitors Containing an
Unusual Trisubstituted Pyridine Core
Mark A. Graham,*,† Steven A. Raw,*,‡ David M. Andrews,† Catherine J. Good,§ Zbigniew S. Matusiak,†
Mark Maybury,§ Elaine S. E. Stokes,† and Andrew T. Turner§
†Oncology Innovative Medicines, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
‡Medicines Evaluation Chemistry, Pharmaceutical Development, AstraZeneca, Charter Way, Macclesfield SK10 2NA, U.K.
§Chemical Science, Pharmaceutical Development, AstraZeneca, Charter Way, Macclesfield SK10 2NA, U.K.
ABSTRACT: A scalable route to histone deacetylase inhibitors containing an unusual 2-aryl-3-cyano-5-aminomethylpyridine
core has been developed which has the flexibility to deliver a range of compounds on at least a multigram scale. The key step
involves a novel Mannich reaction using 3-dimethylaminoacrolein, formaldehyde, and a secondary amine to yield a 2-
(alkylaminomethyl)-3-dimethylaminoacrolein. Tuning of this reaction in process development was fundamental to the success of
the approach in terms of flexibility and operability on scale-up. This new methodology will also enable access an underutilised
family of 3,5-disubstituted pyrid-2-ones and 2,3,5-trisubstituted pyridines.
Scheme 1, we conceived a convergent approach that relied
upon access to two key intermediates: pyridine 5 and boronate
ester 6. The boronate ester 6 should be readily accessible from
7 and 8, which are commercially available. Though Scheme 1
shows (in the forward direction) Suzuki coupling followed by
introduction of the varying amine moiety, we expected the
order of these steps to be interchangeable, affording the desired
flexibility in the route design.
As expected, the formation of boronate ester 6 was
accomplished via coupling of 7 and 8 (Scheme 2). It was
quickly identified that N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N-
methylmorpholinium chloride (DMTMM; 9), prepared in situ
from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-
methylmorpholine, was the coupling agent of choice. A simple
workup gave boronate ester 6 in excellent purity as a free-
flowing white powder, with yield routinely greater than 90%.
With boronate ester 6 in hand, our attention moved to the
coupling partner, pyridine 5. Though the proposed chlor-
omethylpyridine 5b is unknown, there is a single report of the
corresponding aldehyde 5a in the patent literature.4
INTRODUCTION
■
The substituted pyridine motif is ubiquitous in both naturally
occurring and synthetic biologically active molecules. Within
this broad family, the 2,3,5-trisubstituted pyridines are a highly
desirable template for pharmaceutical research.1 Despite this,
synthetic tractability often limits their exploitation in medicinal
chemistry programmes.
As part of a long-standing research programme into the
development of potent, orally dosed inhibitors of histone
deacetylase (HDAc),2 we required access to a range of
compounds of type 1 (Figure 1),2h,j containing the highly
unusual 2-aryl-3-cyano-5-aminomethylpyridine motif. Outside
of our work,2h,j we have identified only one other report of this
structural subunit.3
Preliminary investigation of this synthesis (shown in Scheme
3) showed a Knoevenagel condensation between acetaldehyde
and malononitrile proceeded efficiently,5 but subsequent
conversion to the pyridine proved to be a low yielding,
capricious reaction. Despite several studies into altering the
reaction time, temperature, and base, the highest yield observed
was 35%. The highest yield was achieved by controlled
dropwise addition of the ethylidene nitrile intermediate to
preformed Vilsmeier chloroiminium ion at 90 °C. The reaction
time proved to be critical, and the yield was shown to diminish
if the reaction was heated for more than 1 h. The inherent
thermal instability of the product also had a detrimental impact
in the subsequent Suzuki reaction. Furthermore, an undesirable
exotherm was observed on scale-up of the chloroiminium
Figure 1. General target structure for HDAc inhibitors.
Given the potential that several compounds of type 1 would
be required on a scale of 10 g to 10 kg for preclinical or clinical
studies, any synthetic approach employed should be amenable
to scale-up. The route should ideally allow flexibility in the
order of steps to facilitate optimisation during scale-up
investigations. Furthermore, as a range of structurally similar
compounds were to be prepared, the route should allow a
variety of alkyl amine functionality to be installed with ease.
RESULTS AND DISCUSSION
■
With these requirements in mind, we embarked upon a
retrosynthetic analysis of the general structure 1 in an effort to
define an approach that met these criteria. As depicted in
Received: January 23, 2012
© XXXX American Chemical Society
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Scheme 1. Retrosynthetic Analysis of General Structure 1
Scheme 2. Formation of Boronate Ester 6
Concurrent to investigation of the synthesis of pyridine
aldehyde 5a, we went on to study the Suzuki coupling of the
two key fragments 5a and 6 (Scheme 4) leading to the
advanced biaryl core 4a intermediate.
Scheme 3. Literature Synthesis of Pyridine Aldehyde 5a
Significant optimisation was carried out on this stage. The
reaction, though high-yielding on occasion, again proved to be
capricious. The yield and quality of product depended heavily
on the temperature-control of the reaction (aldehyde 5a
decomposes above 50 °C to a complex mixture of products),
the quality of the catalyst (batches of Strem 1,1′-bis-
(diphenylphosphino)ferrocenedichloropalladium(II) having
chemistry, and difficult chromatography of the final product
would have serious implications for larger scale production.
Scheme 4. Suzuki Coupling To Give the Key Biaryl Core 4a
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Scheme 5. HDAc Inhibitors 1 from 4a via Reductive Amination and Deprotection
Scheme 6. Retrosynthetic Analysis of the Pyridine Fragment
Scheme 7. “Mannich Approach” to 5-Aminomethylpyridines
significantly higher efficacy than others), and the atmosphere
(the reaction appeared to require a rigorously inert
atmosphere). Nevertheless, we did have access to the key
biaryl 4a in sufficient quantities to prepare over 120
compounds of type 1 (for examples, see Scheme 5) for initial
testing.2h,j
Though this initial strategy allowed access to many
compounds of type 1 on a milligram scale, there were
significant issues associated with the approach, as discussed
above. In summary: The synthesis of pyridine aldehyde 5a
remained capricious and low-yielding and employed hazardous
chemistry, the Suzuki coupling was subject to several
limitations, and finally, the use of primary amines in the
reductive amination of 4a proved to be challenging. Primary
amines exhibited low reactivity using the standard sodium
triacetoxyborohydride conditions,6 and the addition of
titanium(IV) isopropoxide was required to drive the reaction
to completion.
The drawbacks outlined above, coupled with demand for
increasingly larger amounts of material for continued testing,
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Scheme 8. Flexible “Mannich Approach”
Figure 2. Calculated pKa values for selected pyridones of type 11.
led us to reconsider our strategy. Specifically, we required an
alternative approach to pyridines of type 5 that avoided the
troublesome Vilsmeier-based approach (Scheme 3). We also
wanted to entirely avoid the use of the thermally unstable
pyridine aldehyde 5a.
In an effort to address these issues, we conceived of an
alternative strategy in which the key biaryl forming Suzuki
reaction would be achieved with 2-chloropyridines already
containing the amine moiety, thus avoiding pyridine aldehyde
5a and circumventing the problematic reductive aminations.
We therefore subjected the generic structure 10 to a
comprehensive retrosynthetic analysis, with the objective of
identifying a route which satisfied the initial requirements of
scalability and flexibility whilst carrying none of the issues
identified above. One attractive approach involved a novel
Mannich transformation and is discussed herein.
As shown in Scheme 6, we envisaged 2-chloropyridines of
type 10 would be available by chlorination of 11. Pyridone 11
should be accessible via a well-precedented condensation of
cyanoacetamide and a 1,3-dicarbonyl or an equivalent such as
12.7 The key step of this proposed approach is the novel
Mannich-type reaction on commercially available 3-dimethyla-
minoacrolein to install the desired aminomethyl moiety.
Though similar transformations have been carried out on
cyclic enaminone-type substrates,8 to our knowledge such a
methodology has thus far not been applied to 3-(dialkylamino)-
acroleins.
Preliminary studies, using N-iso-propylpiperazine as the
amine component, showed this to be a viable approach to
pyridines of type 10 (Scheme 7). We were gratified to find the
key Mannich-type reaction furnished the functionalised acrolein
12a with high conversion. This is the first known example of a
Mannich reaction using an acyclic enaminal or enaminone.
Following condensation and chlorination, the desired chlor-
opyridine 10a was produced in approximately 70% overall yield.
Even more pleasing was the fact that the Suzuki reaction of 10a
and boronic ester 6 proved much more efficient and robust.
However, despite the successes of this “Mannich” approach
to 10a discussed above, it did not meet all of the original
criteria, i.e. a flexible, scalable route to compounds of type 1.
There were two main drawbacks to the synthesis: First, the
pyridone anion 11a could only be isolated by concentration of
the reaction mixture and trituration, operations which are not
particularly amenable to scale-up. This is primarily due to the
zwitterionic nature of the parent hydroxypyridine of 11a, which
did not allow formation of a neutral species. Second, and more
importantly, this approach only gave access to dialkylamino-
methyl pyridines, such as 10a. The use of primary amines, such
as ethylamine, or protected analogues, such as N-benzylethyl-
amine, in the Mannich reaction with dimethylaminoacrolein
resulted only in degradation products, making this route
unusable for synthesis of compounds such as 1b.
Identification of these issues gave us cause to reconsider the
“Mannich approach”, in an effort to exploit its advantages and
avoid the disadvantages, whilst maintaining the desired route
flexibility necessary to respond to demands for 50−500 g-scale
manufacture of compounds of type 1 as and when required.
It was evident to us that the choice of secondary amine
partner would be key to the success of this strategy: First, the
functional group interconversion of substituted benzylamines to
the corresponding benzylchlorides via reaction with alkylchlor-
oformates is well-precedented.9 If an inexpensive, “disposable”
amine could be employed in the Mannich-based synthesis of
10, then such a transformation would allow access to fragment
5b via simple amination of the intermediate 13 (Scheme 8).
This would therefore give us the desired flexibility in terms of
the amine. Furthermore, this modified approach should allow
facile reordering of steps should later development work
identify the need. The various route options are also outlined in
Scheme 8.
Second, judicious choice of amine should also allow us to
address the isolation issues surrounding pyridones of type 11.
As shown in Figure 2, the calculated pKa values10 for pyridones
formed with standard secondary amines, such as diethylamine
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Scheme 9. Morpholine-Based Mannich Approach
Scheme 10. Preliminary Chlorination and Amination Studies
and pyrrolidine (11b and 11c, respectively), indicate
zwitterionic character, with the tertiary amine moiety being
significantly more basic than the pyridone function. The
basicity of morpholine, however, is tempered by the electron-
withdrawing nature of the β-oxygen. The calculated pKa values
for the corresponding pyridone 11d show that the pyridone is
indeed more basic than the amine, by a factor of around 2 pKa
units.
Given that morpholine is inexpensive and readily available,
we chose this as our amine coupling partner. The Mannich
reaction of morpholine with 3-dimethylaminoacrolein gave a
complex mixture of products, of which the major components
12b−e were identified by GCMS (Scheme 9). Presumably, 12c
arises from reaction of either 3-dimethylaminoacrolein or
product 12b with morpholine, liberating dimethylamine. A
Mannich reaction involving 3-dimethylaminoacrolein and
dimethylamine would give 12d. Lastly, minor byproduct 12e
is formed as methanol solvent forms transient oxonium ions
when reacted with formaldehyde under acidic conditions. An
isolated example of this process has been reported.11 Due to the
intractable nature of this mixture, no purification was carried
out at this stage and the mixture was used directly in the
reaction with cyanocetamide. This, in turn, gave the desired
pyridone 11d in acceptable yield after neutralisation with
AcOH. This was accompanied by ether 11e and ammonium
species 11f. These byproducts are, however, efficiently removed
in the workup and isolation of 11d, which crystallises well from
MeCN. Finally, reaction of pyridone 11d with POCl3 in MeCN
gives the chloropyridine 10b.13 It should be noted that the 2-
chloro-3-cyano-5-aminomethyl-pyridine motif exemplified by
compounds 10a and 10b in itself is also biologically relevant,12
yet it too remains poorly represented in the literature.
With the key chloropyridine 10b on hand in sufficient
quantities, we moved on to examine the subsequent trans-
formations (Scheme 10). As shown, preliminary studies
confirmed that the chlorination of 10b was an efficient process,
affording 5b in excellent yield. Unfortunately, removal of the
byproduct morpholine carbamate 13 via nonchromatographic
methods proved challenging.
The reactivity of 5b and its derivatives also proved to be
problematic. Primary amines could be selectively reacted at the
chloromethyl position with careful monitoring of the reaction
conditions, e.g. with ethylamine to give 10c. Secondary amines,
however, were nucleophilic enough to also react at the
chloropyridine position. So, in the case of iso-propylpiperazine,
the sole product formed was the disubstituted species 14. With
ethylamine, the product was shown to dimerise on standing to
give 15.
These preliminary observations allowed us to quickly decide
upon a final strategy, based on our original plans set out in
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Scheme 11. Synthesis of Target Molecules 1b and 1c
Scheme 8: The issues associated with addition of secondary
amines to the chloropyridine position of 5b ruled out
chlorination−substitution−coupling as an approach. We also
decided against the possible chlorination−coupling−substitu-
tion route, as we felt that, under the Suzuki reaction conditions,
there would be significant risk of reaction between 5b and the
product 4b at the amide function, accompanied by dimerization
of 4b via the same mechanism. We therefore moved on to the
latter stages of the project, adopting a coupling−chlorination−
substitution strategy.
Optimisation and scale-up studies of this strategy allowed its
utilisation in the 50 g-scale production of several candidate
APIs of type 1 (Scheme 11). As can be seen, the Suzuki
reaction of the morpholinomethyl chloropyridine 10b and the
boronate ester 6 proceeded in excellent yield, on scales of up to
45 g. Chlorination of this intermediate also proceeded
efficiently, providing 4b on a 66 g scale.
With 4b in hand, we were in position to synthesise large
amounts of candidate APIs that were required, due to the
flexibility inherent in the approach adopted. In the event just
one API was required on medium scale, 35 g of 1b was
produced using this approach. Importantly, the substitution
reaction proved robust and reliable for the primary amines (e.g.,
ethylamine), in contrast to the reductive amination outlined in
Scheme 5. We also gained access to the morpholine analogue
1c by deprotection of intermediate 16.
process development was fundamental to the success of the
approach in terms of flexibility and operability on scale-up. This
approach has so far enabled the efficient synthesis of one API
(1b) on a 35 g scale, as well as two more on a smaller scale (1a
and 1c). In addition, this new methodology will enable
chemists to access an underutilised family of 3,5-disubstituted
pyrid-2-ones and 2,3,5-trisubstituted pyridines.
EXPERIMENTAL SECTION
■
All materials were purchased from commercial suppliers. Unless
specified otherwise, all reagents and solvents were used as
supplied by manufacturers. Nuclear magnetic resonance spectra
were determined using a Jeol JNMEX 400 spectrometer or a
Bruker AM300 spectrometer. All 1H NMR assays were
performed using maleic acid as an internal standard. LCMS
spectra were determined using a Waters Micromass instrument
with a XSELECT CSH C18, 5 μm, 2.1 mm × 50 mm column.
LCMS peak areas were uncalibrated.
Preparation of N-(2-tert-Butoxycarbonylaminophen-
yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzamide (6). To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzoic acid (7) (6.71 g, 26.3 mmol) in
acetontrile (54 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-
triazine (4.98 g, 27.5 mmol) and tert-butyl (2-aminophenyl)-
carbamate (8) (5.37 g, 25.0 mmol). The resulting slurry was
stirred at ambient temperature, and N-methylmorpholine (5.56
g, 6.1 mL, 55.0 mmol) was added dropwise. All the solids
rapidly dissolved, and the resulting solution was stirred at
ambient temperature until analysis by HPLC showed no 8
remained (∼3 h). To this slurry was added water (50 mL),
causing further precipitation. The mixture was stirred for a
further 45 min, and the solid was then collected by vacuum
filtration, washed twice with 50:50 (v/v) acetonitrile/water (2
× 15 mL), and dried in vacuo to a constant weight to yield the
CONCLUSION
■
In summary, a scalable route to HDAc inhibitors containing an
unusual 2-aryl-3-cyano-5-aminomethylpyridine core has been
developed which has the flexibility to deliver a range of API
targets on at least a multigram scale. The key step involves a
novel Mannich reaction using 3-dimethylaminoacrolein, form-
aldehyde, and a secondary amine to yield a 2-(alkylamino-
methyl)-3-dimethylaminoacrolein. Tuning of this reaction in
1
title compound 6 (9.68 g, 86.2%, purity 97.7% (w/w) by H
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NMR assay) as a white solid. 1H NMR (DMSO-d6, 400 MHz)
δ (ppm) 1.30 (12 H, s), 1.42 (9 H, s), 7.16 (2 H, m), 7.55 (2
H, m), 7.82 (2 H, d, J = 8.2 Hz), 7.97 (2 H, d, J = 8.2 Hz), 8.70
(1 H, s), 9.89 (1 H, s). 13C NMR (DMSO-d6, 100 MHz) δ
(ppm) 25.6, 28.9, 80.6, 84.9, 124.8, 125.1, 126.6, 127.0, 127.8,
130.6, 132.6, 135.3, 137.6, 154.4, 166.0.14 LRMS (ESI+) m/z
439 (MH+).
acetonitrile (15 mL). The mixture was heated to 40 °C, and
phosphorous oxychloride (2.48 mL, 26.6 mmol) was added;
then the mixture was heated at 80 °C for 18 h. After cooling to
room temperature, isopropyl alcohol (8 mL) was added, and
the mixture was stirred for 10 min. The mixture was diluted
with water (50 mL) and basified with a solution of sodium
hydroxide (1 M) to pH 8. The product was extracted with
DCM (2 × 100 mL), and the extracts were dried over MgSO4,
filtered, and concentrated to yield the title compound 10a (1.2
Preparation of N-(2-tert-Butoxycarbonylaminophen-
yl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (4a). 2-
Chloro-3-cyano-5-formylpyridine2 (456 mg, 2.74 mmol),
compound 6 (1.2 g, 2.74 mmol), 1,1′-bis(diphenylphosphino)-
ferrocene−palladium(II) dichloride dichloromethane com-
plex15 (112 mg, 0.137 mmol), 1,2-dimethoxyethane (12 mL),
and a saturated aqueous solution of sodium hydrogen
carbonate (6 mL) were stirred at 60 °C under an atmosphere
of nitrogen for 7.5 h. The mixture was allowed to cool before
being partitioned between dichloromethane and water. The
organics were separated, dried over Na2SO4, filtered, and
evaporated. The crude product was purified by chromatography
on silica, eluting with 40:60 ethyl acetate/isohexane to yield the
title compound 4a (615 mg, 51%, 95% purity by LCMS area)
as a cream solid. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.46
(9 H, s), 7.20 (2 H, m), 7.58 (2 H, td, J = 1.45, 6.91, 6.01 Hz),
8.11 (2 H, d, J = 8.54 Hz), 8.17 (2 H, d, J = 8.54 Hz), 8.70 (1
H, s), 8.92 (1 H, d, J = 2.01 Hz), 9.40 (1 H, d J = 2.01 Hz),
9.98 (1 H, s), 10.20 (1 H, s). 13C NMR (DMSO-d6, 100 MHz)
δ (ppm) 24.9, 28.0, 73.5, 79.6, 107.9, 116.8, 123.7, 124.0, 125.8,
126.2, 127.9, 129.3, 129.4, 132.0, 136.3, 139.2, 143.0, 153.4,
162.5, 164.7, 190.6. LRMS (ESI+) m/z M + Na+ 465.
1
g, 81%, purity 95% by LCMS area) as a brown oil. H NMR
(CDCl3, 300 MHz) δ (ppm) 1.05 (6 H, d, J = 6.6 Hz), 2.49 (4
H, m), 2.55 (4 H, m), 2.67 (1 H, m), 3.52 (2 H, s), 8.02 (1 H,
d, J = 2.3 Hz), 8.50 (1 H, d, J = 2.3 Hz); LRMS (ESI+) m/z
279/281 (MH+).
Preparation of tert-Butyl {2-[(4-{3-Cyano-5-[(4-isopro-
pylpiperazin-1-yl)methyl]pyridin-2-yl}benzoyl)amino]-
phenyl}carbamate (Boc-1a). 1,1′-Bis(diphenylphosphino)-
ferrocenedichloropalladium(II) chloride15 (58 mg, 0.072
mmol) was added to a mixture of 6 (626 mg, 1.43 mmol),
10a (398 mg, 1.43 mmol), saturated aqueous sodium hydrogen
carbonate solution (5 mL), and 1,2-dimethoxyethane (10 mL).
The mixture was heated at 80 °C for 1 h and then allowed to
cool to room temperature and partitioned between dichloro-
methane (75 mL) and water (50 mL). The aqueous layer was
extracted with further dichloromethane (2 × 75 mL). The
combined organics were dried over magnesium sulfate, filtered,
and then evaporated to dryness. The residue was purified by
flash chromatography on silica, eluting with methanol (5−10%)
in dichloromethane to yield the title compound Boc-1a (652
mg, 82%, purity 100% by LCMS area) as a yellow gum which
crystallised on trituration with diethyl ether. 1H NMR (DMSO-
d6, 400 MHz) 1.02 (6 H, d, J = 6.5 Hz), 1.50 (9 H, s), 2.50 (8
H, m), 2.69 (1 H, m), 3.67 (2 H, s), 7.25 (2 H, m), 7.62 (2 H,
m), 8.07 (2 H, d, J = 8.5 Hz), 8.18 (2 H, d, J = 8.5 Hz), 8.38 (1
H, d, J = 2 Hz), 8.76 (1 H, s), 8.93 (1 H, d, J = 2 Hz), 10.00 (1
H, s); 13C NMR (DMSO-d6, 100 MHz) δ (ppm) 18.6, 28.4,
48.3, 53.1, 54.1, 58.2, 80.0, 107.1, 117.9, 124.1, 124.4, 126.1,
126.6, 128.2, 129.3, 129.9, 132.4, 133.8, 135.8, 140.4, 142.5,
153.8, 158.1, 165.2, 165.8; HRMS (ESI+) m/z 555.30786
(MH+).
Preparation of N-(2-Aminophenyl)-4-[3-cyano-5-[(4-
isopropylpiperazin-1-yl)methyl]-2-pyridyl]benzamide
(1a). Boc-1a (344 mg, 0.621 mmol) was dissolved in methanol
(10 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxan
(10 mL) addedm and then the solution was stirred at 22 °C for
2 h. The solvent was evaporated, and then methanol (5 mL)
was added and the resulting solution absorbed onto an SCX-2
column, which was then washed with methanol (2 column
volumes) and eluted with a 2 M solution of ammonia in
methanol (2 column volumes). The ammonia/methanol
solution was concentrated in vacuo to give a foam. This was
treated with diethyl ether (20 mL), stirred, and filtered to yield
the title compound 1a (161 mg, 57%, 96% purity by LCMS
area) as a white solid. 1H NMR (DMSO-d6, 500 MHz) 0.95 (6
H, d, J = 6.4 Hz), 2.44 (8 H, m), 2.60 (1 H, m), 3.60 (2 H, s),
4.94 (2 H, s), 6.60 (1 H, dt, J = 1.4, 7.6 Hz), 6.79 (1 H, dd, J =
1.4, 7.6 Hz), 6.98 (1 H, dt, J = 1.4, 7.6 Hz), 7.20 (1 H, m), 7.98
(2 H, d, J = 8.3 Hz), 8.14 (2 H, J = 8.3 Hz), 8.30 (1 H, J = 2.1
Hz), 8.86 (1 H, d, J = 2.1 Hz), 9.78 (1 H, s); 13C NMR (125
MHz, DMSO) δ 18.2, 47.9, 52.9, 53.5, 57.8, 66.3, 106.6, 116.0,
116.1, 117.6, 123.0, 126.7, 127.9, 128.7, 133.3, 135.7, 139.5,
142.1, 143.2, 153.4, 157.8, 164.7; LRMS (ESI+) m/z 455
(MH+).
Preparation of (2E)-3-(Dimethylamino)-2-[(4-isopro-
pylpiperazin-1-yl)methyl]acrylaldehyde (12a). 1-Isopro-
pylpiperazine (4.4 mL, 30.6 mmol) was added to a solution of
3-(dimethylamino)acrolein (2.82 g, 25.5 mmol) in ethanol
(100 mL), followed by formaldehyde (37% solution in water,
2.3 mL, 30.6 mmol) and acetic acid (100 μL). The mixture was
stirred at 50 °C for 3.5 h and then room temperature for 15 h.
The solution was concentrated in vacuo and redissolved in
ethanol (25 mL), and then formaldehyde (2.3 mL) and acetic
acid (100 μL) were added. The mixture was stirred at 60 °C for
4 h and then concentrated in vacuo to yield the title compound
12a (6.10 g, 90%, purity 99% by LCMS area) as a pale yellow
oil. 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.03 (6 H, d, J = 6.4
Hz), 2.51 (8 H, m), 2.67 (1 H, m), 3.18 (2 H, s), 3.26 (6 H, s),
6.62 (1 H, s), 8.89 (1 H, s); LRMS (ESI+) m/z 240 (MH+).
Preparation of Sodium 3-Cyano-5-[(4-isopropylpiper-
azin-1-yl)methyl]pyridin-2-olate (11a). 2-Cyanoacetamide
(5.36 g, 63.7 mmol) was added to a solution of 12a (6.10 g,
25.5 mmol) in ethanol (150 mL), followed by dropwise
addition of sodium ethoxide (21% solution in ethanol, 28.6 mL,
76.5 mmol) over 5 min. The solution was heated at reflux for
17 h and then cooled to room temperature. The yellow solid
was filtered, and the filtrate was concentrated in vacuo. The
residue was triturated with diethyl ether, and the solid obtained
was dried to yield the title compound 11a (8.74 g, purity 90%
by LCMS area) as a pale yellow solid, which was used without
1
further purification. H NMR (DMSO-d6, 300 MHz) δ (ppm)
0.92 (6 H, d, J = 6.6 Hz), 2.27 (4 H, m), 2.38 (4 H, m), 2.55 (1
H, m), 3.10 (2 H, s), 7.24 (1H, d, J = 2.8 Hz), 7.74 (1 H, d, J =
2.8 Hz); LRMS (ESI+) m/z 261 (MH − Na+).
Preparation of 2-Chloro-5-[(4-isopropylpiperazin-1-
yl)methyl]nicotinonitrile (10a). A 4.0 M solution of
hydrogen chloride in dioxane (1.33 mL, 5.31 mmol) was
added to a stirred suspension of 11a (1.5 g, 5.31 mmol) in
G
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Preparation of 5-(Morpholin-4-ylmethyl)-2-oxo-1,2-
dihydropyridine-3-carbonitrile (11d). Aqueous formalde-
hyde (12.3 M, 29.0 mL, 357.3 mmol) was added to a solution
of N,N-dimethylamino-2-propen-1-al (30.0 mL, 29.70 g, 299.6
mmol) in methanol (150 mL). The stirrer was started, and
morpholine (31.0 mL, 30.97 g, 355.5 mmol) was added in three
approximately equal portions (CAUTION: a large exotherm is
observed over the course of this addition of approximately 30
°C). Once the temperature was stabilised, acetic acid (2.10 mL,
2.20 g, 36.7 mmol) was added. The resulting orange solution
was then heated to gentle reflux and stirred until analysis by GC
indicated complete consumption of starting material (∼2.5 h).
The reaction mixture was then cooled to 22 °C and
concentrated in vacuo to a brown oil. GCMS analysis showed
this to comprise the following: 12b, 66.0 area %; 12c, 12.9 area
%; 12d, 5.5 area %; 12e, 3.8 area %. The oil was dissolved in
IMS (340 mL) and transferred to a flask containing 2-
cyanoacetamide (62.84 g, 747.5 mmol). To the stirred
suspension was added 21% (w/w) sodium ethoxide in IMS
(335.0 mL, 897.3 mmol). The mixture was warmed to gentle
reflux and stirred until analysis by GC showed complete
consumption of 12b−e (∼4 h). The mixture was then cooled
to 40 °C and water (890 mL) was added, causing all solids to
dissolve, followed by acetic acid (52.0 mL, 54.5 g, 907.5 mmol).
The resulting mixture was transferred to a separating funnel
and washed with water (70 mL). This was extracted three times
with DCM (3 × 270 mL), and the combined organics was
concentrated in vacuo to afford an orange solid. This solid was
then suspended in acetonitrile (360 mL) and stirred for 1 h.
The solid was then collected by vacuum filtration, washed twice
with acetonitrile (2 × 100 mL), and dried in vacuo to a
constant weight to give the title compound 11d (26.01 g,
38.1%, purity 96.1% (w/w) by 1H NMR assay), as a red/brown
solid. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 2.33 (4 H, m),
3.23 (2 H, s), 3.55 (4 H, m), 7.66 (1 H, d, J = 2.6 Hz), 8.06 (1
H, d, J = 2.6 Hz); 13C NMR (DMSO-d6, 100 MHz) δ (ppm)
52.6, 57.2, 66.1, 103.0, 114.8, 116.4, 140.8, 150.4, 159.8; HRMS
(ESI+) m/z 220.10806 (MH+). Calc 220.10805.
Hz); 13C NMR (DMSO-d6, 100 MHz) δ (ppm) 52.7, 57.6,
66.0, 109.3, 115.0, 133.8, 143.9, 149.7, 153.6; LRMS (ESI+) m/
z 238/240 (MH+).
Preparation of 2-Chloro-5-(chloromethyl)-
nicotinonitrile (5b). To a stirred solution of 10b (8.00 g,
33.56 mmol) in THF (80 mL) was added ethyl chloroformate
(4.00 mL, 4.54 g, 41.83 mmol). The solution was heated to
reflux for 23 h. HPLC indicated the reaction had gone to
approximately 90% completion. A further portion of ethyl
chloroformate (2.40 mL, 2.72 g, 25.1 mmol) was added, and
the solution was heated to reflux for a further 19 h. The
solution was cooled to 25 °C and then poured into a mixture of
potassium bicarbonate (56.06 g, 112.0 mmol) and ethyl acetate
(120 mL). The flask was rinsed with ethyl acetate (40 mL).
The phases were separated, and the organics were then washed
with water (2 × 20 mL) and brine (40 mL) and then
concentrated in vacuo. The residue was triturated with MTBE
(30 mL), and the colourless solid was removed by filtration.
The organic solution was concentrated in vacuo to yield 5b
(13.59 g; 32.84 mmol, 97.9%, purity 45.2% (w/w) by 1H NMR
1
assay) as an orange oil. H NMR (DMSO-d6, 400 MHz) δ
(ppm) 4.86 (2 H, s), 8.60 (1 H, d, J = 2.4 Hz), 8.79 (1 H, d, J =
2.4 Hz); 13C NMR (DMSO-d6, 100 MHz) δ (ppm) 41.0, 109.8,
114.6, 133.7, 144.0, 150.7, 153.4.
Preparation of 2-Chloro-5-[(ethylamino)methyl]-
nicotinonitrile (10c). Ethylamine (2.0 M solution in THF,
2.30 mL, 4.60 mmol) was added to 5b (445 mg, 1.16 mmol),
resulting in the formation of a suspension. This was stirred at
22 °C for 2 h. The mixture was poured into water (7 mL) and 2
M hydrochloric acid solution (2 mL, 4 mmol); then it was
washed with ethyl acetate (5 mL). The aqueous solution was
basified with 2 M sodium hydroxide solution (5 mL, 10 mmol)
and then extracted with ethyl acetate (10 mL). The organics
were washed sequentially with water (5 mL) and brine (5 mL)
and then concentrated in vacuo. To the residue was added
MTBE (2 mL), and then the solid was removed by filtration
and washed with MTBE (1 mL). The combined organics were
then concentrated in vacuo to yield 10c (217 mg, 0.902 mmol,
1
78.1%, purity 81.4% (w/w) by H NMR assay) as a yellow oil.
Preparation of 2-Chloro-5-(morpholin-4-ylmethyl)-
nicotinonitrile (10b). To a stirred suspension of 11d (24.95
g, 109.4 mmol) in acetonitrile (250 mL) was added phosphoryl
chloride (20.5 mL, 33.82 g, 220.6 mmol) over 10 min. The
mixture was heated to gentle reflux and stirred for 18 h. The
mixture was cooled to 0−5 °C, and a suspension formed. To
this mixture was added a 3.0 M NaOH solution (365 mL, 1.10
mol) dropwise over 30 min: CAUTION: this addition is
exothermic. To this slurry was then added DCM (250 mL), and
the solid was removed by filtration. The cake was washed with
DCM (125 mL). The resulting biphasic mixture was separated
and the aqueous layer extracted with further DCM (125 mL).
The combined organics were washed sequentially with water
(125 mL) and brine (125 mL) and then concentrated in vacuo
to give a brown solid. This solid was suspended in MTBE (375
mL) and warmed to reflux for 45 min. The solids were removed
by hot vacuum filtration, and the residues were washed with hot
MTBE (50 mL). The combined MTBE solution was allowed to
cool slowly to ambient temperature, and the product
crystallised. The solid was collected by vacuum filtration and
washed with MTBE (50 mL) and dried in vacuo to give the title
compound 10b (15.45 g, 64.8 mmol, 59.3%, purity 99.1% (w/
1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.02 (3 H, t, J = 6.9
Hz), 2.49 (2 H, m), 3.54 (1 H, m), 3.74 (2 H, s), 8.39 (1 H, d, J
= 2.4 Hz), 8.64 (1 H, d, J = 2.4 Hz); 13C NMR (DMSO-d6, 100
MHz) δ (ppm) 14.9, 42.7, 48.5, 109.0, 115.1, 136.9, 143.1,
149.0, 152.9. LRMS (ESI+) m/z 196/198 (MH+).
Preparation of tert-Butyl [2-({4-[3-Cyano-5-(morpho-
lin-4-ylmethyl)pyridin-2-yl]benzoyl}amino)phenyl]-
carbamate (16). To a solution of 10b (35.0 g, 150 mmol) and
6 (64.7 g, 150 mmol) in 1,2-dimethoxyethane (1000 mL) was
added 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium-
(II) (5.0 g, 6.83 mmol), followed by saturated sodium
bicarbonate solution (23 mL). The reaction mixture was
degassed with nitrogen for 5 min and then heated to 80 °C for
4 h. The reaction mixture was diluted with water and extracted
with dichloromethane. Dichloromethane extracts were com-
bined, dried over magnesium sulphate, and concentrated. The
crude product was purified by flash chromatography (eluting
with ethyl acetate/isohexane) to yield 16 (87.6 mmol, 45.0 g,
1
58%, purity 96% by area LCMS) as a white solid. H NMR
(400 MHz, DMSO-d6) δ 1.47 (9 H, s), 2.42−2.46 (4 H, m),
3.57−3.62 (4 H, m), 3.64 (2 H, s), 7.16−7.19 (1 H, m), 7.22−
7.25 (1 H, m), 7.58−7.61 (2 H, m), 8.03−8.05 (2 H, m), 8.14−
8.16 (2 H, m), 8.37 (1 H, d, J = 1.9 Hz), 8.72 (1 H, s), 8.92 (1
H, d, J = 1.9 Hz), 9.97 (1 H, s). 13C NMR (100 MHz, DMSO-
1
1
w) by H NMR assay), as a yellow crystalline solid. H NMR
(DMSO-d6, 400 MHz) δ (ppm) 2.38 (4 H, m), 3.56 (2 H, s),
3.58 (4 H, m), 8.38 (1 H, d, J = 2.3 Hz), 8.63 (1 H, d, J = 2.3
H
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Article
d6) δ 29.0, 53.9, 59.1, 67.0, 80.5, 107.7, 118.4, 124.6, 124.9,
126.6, 127.1, 128.7, 129.8, 130.4, 132.9, 134.0, 136.4, 140.8,
143.2, 154.3, 154.4, 158.6, 165.0. LRMS (ESI−) m/z 514 ([M
− H]−).
139.6, 141.4, 143.3, 152.9, 157.4, 164.8; LRMS (ESI+) m/z 372
(MH+).
AUTHOR INFORMATION
Corresponding Author
Mark.A.Graham@astrazeneca.com; Steven.Raw@astrazeneca.
com
■
Preparation of tert-Butyl [2-({4-[5-(Chloromethyl)-3-
cyanopyridin-2-yl]benzoyl}amino)phenyl]carbamate
(4b). To a solution of 16 (26.0 g, 50.6 mmol) in THF (250
mL) was added ethyl chloroformate (14.5 mL, 151.8 mmol)
dropwise over 5 min. The reaction was heated at reflux
temperature for 18 h. The reaction mixture was cooled to 25 °C
and then added to ethyl acetate (500 mL) and saturated
sodium bicarbonate solution (350 mL). The layers were
partitioned, and then the aqueous layer was extracted with ethyl
acetate (2 × 350 mL). Combined organics were dried over
magnesium sulfate and then concentrated. The crude product
was purified by flash chromatography (eluting with ethyl
acetate/isohexane) to yield 4b (36.7 mmol, 17.3 g, 74%, purity
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors would like to thank Stuart Hunter, Olivier
Germay, and Lorraine Graham for analytical support.
■
REFERENCES
■
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(13) The reaction conditions used for the synthesis of 11d and 10b
are unoptimised, and the variation in yield is mainly due to variation in
workup procedure.
(14) In this 13C spectrum, there should be 16 carbon signals.
However, the carbon bonded to boron cannot be seen in this
spectrum, so only 15 carbons are published. This can be explained
because naturally occurring boron has a 11B/12B ratio of 80:20. 11B has
a spin of 3/2, and 12B has a spin of 3. This leads to complicated
splitting patterns imparted to the carbon bonded to it (80% split into a
quartet, 20% split into a heptet). As the carbon is also a weak
quaternary signal, this splitting has the effect of diluting the signal into
the background. This effect is short-range, so it does not manifest itself
in the other signals. In effect, we cannot see the missing carbon in the
spectrum.
(15) 1,1′-Bis(diphenylphosphino)ferrocene−palladium(II)dichloride
can be readily exchanged with 1,1′-bis(diphenylphosphino)ferrocene−
palladium(II)dichloride dichloromethane complex without significant
impact on the Suzuki reaction. The catalyst was chosen on the basis of
availability at the time of the experiment.
J
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