A simplified process for the manufacture of AZD0530, a potent SRC kinase inhibitor

Article abstract of DOI:10.1021/op200079g

An efficient process for the manufacture of AZD0530 1, a potent SRC kinase inhibitor, has been developed. The key transformation, reaction of monofluoroanilide 7 with alcohol 8, was much simplified between manufacturing campaigns. The development of a robust, efficient, and scalable process for this transformation drew on both a practical and theoretical understanding of the process and is described herein

Full text of DOI:10.1021/op200079g

ARTICLE
pubs.acs.org/OPRD
A Simplified Process for the Manufacture of AZD0530, a Potent SRC
Kinase Inhibitor
Steven A. Raw,* Brian A. Taylor, and Simone Tomasi
Pharmaceutical Development, AstraZeneca, Charter Way, Macclesfield, SK10 2NA, U.K.
ABSTRACT: An efficient process for the manufacture of AZD0530 1, a potent SRC kinase inhibitor, has been developed. The key
transformation, reaction of monofluoroanilide 7 with alcohol 8, was much simplified between manufacturing campaigns. The
development of a robust, efficient, and scalable process for this transformation drew on both a practical and theoretical
understanding of the process and is described herein
1
’
INTRODUCTION
Scheme 1. Large-scale manufacturing route to AZD0530
Previous communications have disclosed the development of
1
an expedient process for the manufacture of multikilogram
quantities of AZD0530 1, a potent SRC kinase inhibitor for
2
the treatment of solid tumours. This route comprised the
conversion of readily accessible quinazolone 2 to the correspond-
ing chloroquinazoline 3, followed by three consecutive S Ar
N
reactions with 4, 6, and 8, exploiting the differing reactivities of
the halogens decorating chloroquinazoline 3 (Scheme 1). The
synthesis outlined in Scheme 1 varies from that used for our first
1c
multikilogram-scale manufacture of AZD0530 1 in one respect:
that tert-amyl alcohol is employed as solvent in the transforma-
tion of 7 to 1 instead of diethoxyethane for toxicological and
environmental reasons. This change was made between pilot
plant campaigns, and the tert-amyl alcohol process was success-
fully carried out on a >100 kg scale.
This manufacturing route was concise, and most of the stages
were considered satisfactorily robust for potential technical
transfer to a commercial manufacturing unit. However, the final
SNAr reaction, transformation of monofluoroanilide 7 into
AZD0530 1, was not fully optimized, primarily due to time
constraints.
The key issues with the process as it stood at the time were:
(
1) use of a protic solvent of apparently similar pK to the
a
alcohol 8; (2) significant levels of unidentified byproducts, as
observed by HPLC, if the batch temperature was allowed to rise
above 90 °C; (3) a high charge of alcohol 8 (3.1 mol equiv) was
required to achieve acceptable reaction times (contributory to
this was the upper limit on reaction temperature); (4) the
hitherto unexplained requirement for a charge of “magic water”
equimolar to the charge of sodium tert-amylate to suppress
byproduct formation (this water charge was also required when
aprotic solvents such as diethoxyethane were employed); (5)
the process was operationally complex, with a high number of
operations, including two vacuum distillations, low minimum
volumes, and an accurate pH adjustment; (6) a relatively low
isolated yield (average of 63% over four batches) with an un-
acceptably high loss to liquors (approximately 8% of theo-
retical); and (7) the isolation of AZD0530 1 as a trihydrate
which dehydrated easily, became friable, and rehydrated to
varying levels.
’ RESULTS AND DISCUSSION
The beginning of a further manufacturing campaign to sup-
port phase II and III trials, requiring delivery of 280 kg of API,
gave us the opportunity to redevelop the synthesis of AZD0530 1
from monofluoroanilide 7 and address some, if not all, of these
issues.
A preliminary solvent screen showed that the aromatic
solvents anisole, toluene, and chlorobenzene gave similar reac-
tion profiles to that seen with tert-amyl alcohol, under compar-
able conditions. With little to choose between these solvents in
terms of reaction profile, toluene was chosen for further study
based on practical considerations (e.g., toxicity, environmental
impact, density, and boiling point).
1
c
Received: March 29, 2011
Published: April 20, 2011
r 2011 American Chemical Society
688
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|Org. Process Res. Dev. 2011, 15, 688–692

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We then undertook a factorial experimental design study,
intended to optimize the reaction parameters in toluene, using
Fractional Factorial Design with 4 factors, each set at 2 levels3,
Resolution IV, with 2 centre points, a total of 10 experiments.
The results from this are summarized below:
A thorough conformational analysis revealed that the most
stable geometry of neutral 8 was the chair conformation, with
both the methyl and the ꢀCH CH OH substituents equatorial.
2
2
The same geometry is found in the alkoxide of 8, if the sodium
cation is not considered, as shown in Figure 1 a. When the cation
is included explicitly in the calculations, another conformation
for the alkoxide of 8 is found to be most stable. This has the
piperazine ring in a boat conformation, with the two ring
substituents pseudo-equatorial and the ꢀCH CH ONa group
•
•
•
•
The charge of base had little effect on reaction outcome
when above 2.20 mol equiv. The range explored was 2.20 to
3
.60 mol equiv.
The stoichiometry of the water charge is crucial. Charges
greater than equimolar to base stoichiometry significantly
reduce the rate of reaction.
Higher temperatures give an increased rate of reaction but
higher levels of impurities. This can be tempered by slight
increases in water charge.
Increasing the stoichiometry of alcohol 8 increases the
reaction rate. Ideally, however, this charge would be mini-
mized to minimize cost.
2
2
þ
folded onto itself, bringing the Na into a position where it is
capable of interacting with the lone pairs of both nitrogen atoms,
as shown in Figure 1 b. This chelation provides enhanced stability
to the alkoxide of 8 relative to the non-chelated mode, calculated
as a ΔG° of 2.8 kcal/mol at 363 K, or 1.7 pK units.
a
Sodium tert-Amylate. Whilst sodium tert-amylate is clearly an
adequate base for the deprotonation of 8 in pure toluene, the
presence of water equimolar to the base makes it questionable that
sodium tert-amylate is present in the reaction environment. It is
much more likely that NaOH is actually present, due to the
hydrolysis of sodium tert-amylate to tert-amyl alcohol and NaOH.
It is well known that hydroxide is a weaker base than alkoxides in
With this basic understanding of the practicalities of the
reaction, we sought to explore the nature of the species
present in an effort to fully comprehend the process. To do
this, we embarked upon the in silico modeling of the species
involved. Relative basicities in the gas phase and in toluene
were computed using Density Functional Theory (DFT).
Solvation effects were estimated using PCM (Polarizable
Continuum Model). The calculations were performed for a
range of temperatures, but only the results for 363 K (90 °C)
are reported here:
4
aqueous solution, with high solvation in water mitigating its
basicity. This is not the case for other solvents, which are not as
capable of solvating it. Table 1 shows the proton affinities of
hydroxide and tert-amylate anions in the gas phase and in toluene
solution. In all cases the effect of the cation is ignored.
Table 1. Calculated proton affinities at 298 K
Alcohol 8. tert-Amyl alcohol was found to be a weaker acid,
compared to alcohol 8. Its deprotonation in toluene is 4.7 kcal/
ΔG (or
ꢀ
mol more energetic than that of 8, corresponding to a ΔpK of
OH
tert-Amylate
ΔΔGSolv)
a
2
.8 units. Since tert-amyl alcohol is the weaker acid, its conjugate
Gas phase (calc)
Gas phase (expt)
Toluene
ꢀ384.9
ꢀ383.7
ꢀ334.6
ꢀ51.4
ꢀ367.2
ꢀ366.5
ꢀ335.7
ꢀ32.6
17.7
17.2
ꢀ1.1
18.8
base, tert-amylate, is capable of deprotonating 8. Further to that,
we found that internal chelation operating in the alkoxide of 8
5
(
vide infra) plays an important role in the stability of the sodium
ΔGSolv toluene
alkoxide (Figure 1), contributing to increasing the acidity of 8
beyond that expected for a standard primary alcohol.
In the gas phase the hydroxide anion is a much stronger base
than tert-amylate. Comparison with accurate experimental pro-
5
ton affinities demonstrates the reliability of the gas-phase in silico
results. In toluene, the two bases are of approximately equal
strength (tert-amylate being marginally stronger). This is due to
the much larger solvation energy of hydroxide. In a highly polar
solvent like water, the difference would be even larger, making
hydroxide a much weaker base compared to tert-amylate.
Substrate and Product. The last point of the in silico
investigation was to assess the basicity of monofluoroanilide 7
and AZD0530 1, as both species possess a relatively acidic anilide
proton. The calculations showed that the anilide protons of 7 and
1
are more acidic than the OH proton of alcohol 8. Deprotona-
tion of 7 with hydroxide is 20.6 kcal/mol exergonic in toluene at
3
63 K; while under the same conditions deprotonation of 8 is
6.7 kcal/mol exergonic (including the chelate effect). As expected,
the anilide proton of 1 is less readily available than that of 7, due to
the different substitution pattern (the electron-withdrawing F-sub-
stituent of 7 has been replaced by an electron-donating alkoxy
group in 1). Practically, this means that 1 equiv of base is consumed
by deprotonation of the substrate, before deprotonation of alcohol
8
is possible. This is in accordance with the FED observation that at
least 2 mol equiv of base are required for acceptable reaction rates.
These results suggested to us that in the absence of water NaOH
should be a valid substitute for sodium tert-amylate as a base for
this process, especially considering that the aforementioned
Figure 1. Conformational stability in the alkoxide of side chain 8.
6
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Organic Process Research & Development
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chelate effect makes the deprotonation of 8 more favored than
that for a normal primary alcohol. Removal of the water formed
during the deprotonation of 7 and 8 by NaOH may also be
alcohol in situ, the reaction profile observed by HPLC was
significantly worse than the newly devised process. To this end,
we carried out a series of experiments using the new conditions
that included a charge of tert-amyl alcohol in increasing amounts.
These showed that, as the charge of tert-amyl alcohol increased, so
the HPLC profile deteriorated. Many of the impurities observed
were those arising from hydrolysis of the monofluoroanilide 7 and
AZD0530 1, at several positions. We presume that the alcohol in
some way solubilizes the hydroxide ions in toluene, thus promot-
ing hydrolysis pathways, whereas in the alcohol-free system any
unreacted hydroxide remains in the solid phase.
beneficial to reactivity. The relative pK values resulting from
a
these in silico calculations are summarized in Figure 2.
We proved very early in this phase of development that the
trihydrate form of AZD0530 1 could be crystallized from the
toluene reaction mixture, albeit after a significant quantity of
water (e.g., 2 relative volumes) was charged. As discussed in the
Introduction, however, this morphology was problematic in
terms of processing. A short investigation showed that a new,
anhydrous form of AZD0530 1 could easily be isolated from the
toluene mixture, providing it was dried azeotropically prior to
crystallization. We also showed that seeding the mixture at
saturation point and subsequent slow addition of heptane
antisolvent gave excellent control of the crystallization process.
This anhydrate of 1 proved stable up to 95% relative humidity.
The changes discussed above combined to make a robust,
much-simplified process. These improvements also saw a sig-
nificant increase in isolated yield from 63% to g80%, with the
losses to liquors being e1% of theoretical. The process is also
now much simpler from an accommodation perspective, with a
reduced number of operations. The process flow is outlined in
the schematic below (Figure 3)
Figure 2. Relative basicities in toluene at 363 K with approximate ΔpKa
values.
The learning from the theoretical study of this reaction is
summarized below:
•
•
•
•
Both sodium tert-amylate and NaOH are basic enough to
deprotonate alcohol 8 in anhydrous toluene at 363 K
(
90 °C).
þ
The internal chelation of the Na cation in the alkoxide of 8
makes a large contribution to the enhanced acidity of 8
relative to a normal primary alcohol.
At least 2 equiv of base are required for the transformation as
both 7 and 1 are more acidic than 8 and therefore consume
the first equivalent of base charged.
The presence of water when using sodium tert-amylate will
lead to the hydrolysis of the alkoxide to give aqueous NaOH,
which is a weaker base and not capable of completely
deprotonating 8.
Given the now considerable understanding we had of the
processes involved in the conversion of monofluoroanilide 7 into
AZD0530 1, both practical and theoretical, we decided to pursue
a water-free process using NaOH as base and toluene as solvent
for further development.
We quickly established that this system gave a much better
reaction profile by HPLC than the existing tert-amyl alcohol
system and the upper reaction temperature limit of 90 °C was no
longer applicable. The reaction was successful even at reflux
temperature (approximately 109 °C), though an operating range
of 104ꢀ106 °C was deemed preferable when energy consump-
tion at a large scale was considered. The increased temperature
and the simplified reaction system meant that the charge of
alcohol 8 could be more than halved, from 3.2 to 1.5 mol equiv,
though the process is typically carried out with a 1.7 mol equiv
charge to ensure robustness. The reaction time was also halved,
from 18 to 9 h.
As the water-free system had proved to be beneficial to the
process, we also explored the continuous removal of the water
formed in situ by means of a DeanꢀStark apparatus. This indeed
proved to be advantageous in terms of reaction rate, reducing
reaction times to 5 h, as opposed to 9 h, and this may have
delivered further reductions in the charge of alcohol 8. However,
we found that, under these “anhydrous” conditions, reaction
mixtures were impractically thick, to the point of being immobile.
We propose that the mole equivalent of water liberated in situ
serves to solubilize some of the anionic species present, though
we have no evidence as to which or of the precise mechanism.
We were also keen to understand why, if in the original process
the charge of “magic water” simply produced NaOH and tert-amyl
Figure 3. A schematic outline of the new process.
In the final phases of development, our focus turned to identifica-
tion of the byproducts from this S Ar reaction, in an effort to gain a
N
full understanding of the process. We succeeded in this, with all
significant byproducts being characterized (by LCMS at least) and
many being synthesized independently (9, 10, 11, and 15). We
believe that these identified species account for the remaining mass
balance of the reaction (Scheme 2). Furthermore, a good under-
standing of the identity of these byproducts allowed us to make a
thorough evaluation of the process against structural alerts for
6
mutagenicity, an important consideration given AZD0530 1 is
the API. In the event, only cyanoaniline 15 gave a structural alert, but
this was proven to be non-genotoxic by subsequent synthesis and
5-strain GLP Ames testing (in the presence and absence of S9)
7
using the plate incorporation method.
The majority of these byproducts (9, 10, 11, 13, and 14) are
removed by water washes once the reaction is complete, as are
6
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Organic Process Research & Development
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Scheme 2. Typical reaction outcome in the synthesis of AZD0530 1
unreacted alcohol 8 and the inorganic salts. The subsequent
crystallization rejects the remainder (12 and 15). A small amount
of monofluoroanilide 7 persists in the isolated AZD0530 1, but
this is totally rejected in a subsequent crystallization process in
then adjusted to 70 °C over 30 min, and a sample was taken for
analysis to confirm satisfactory conversion.
In a separate 1500 L glass-lined mild-steel vessel, equipped
with a baffle and retreat curve agitator, water (510 L) was warmed
to 75 °C, ready for use. 290 L of this warm water were charged to
the reaction mixture, causing an exotherm of 6 °C. The mixture
was stirred at 70 °C for 30 min, and then the agitator stopped.
The mixture was allowed to equilibrate for 30 min, and then the
lower, aqueous phase was removed and discarded. This washing
procedure was repeated twice more with the remainder of the
warm water, first with 145 L and last with 75 L. The upper organic
phase was retained in the reactor and concentrated by distillation
1
which the difumarate salt of AZD0530 1 is formed.
’
CONCLUSIONS
By the effective integration of learning from factorial experi-
mental design studies, in silico theoretical analyses, and subse-
quent focused laboratory experimentation, we have rapidly
developed an operationally simple, robust process for the con-
version of monofluoroanilide 7 into AZD0530 1. We have
addressed all of the issues associated with the anteceding
processes and, concurrently, gained an excellent understanding
of the current process. The improved process has been employed
in a pilot plant campaign of AZD0530 1, delivering 300 kg of
material over four batches in an overall yield of 80%.
(
at a pressure of 1 bar) to a volume of 250 ( 20 L.
The resulting solution was then cooled to 90 °C and trans-
ferred from the reactor to the crystallizer, a 1000 L glass-lined
mild-steel vessel, equipped with a baffle and retreat curve
agitator, followed by a line wash of toluene (50 L). The contents
of the crystallizer were adjusted to 65 °C, and AZD0530 1 seed
material (0.363 kg, 0.5 wt %) was added. The batch was allowed
to equilibrate for 3 h, and then heptane (288 L) was charged via
an orifice plate over 2 h, maintaining the temperature at
63ꢀ67 °C. The resulting slurry was held for 1 h and then cooled
from 65 to 17 °C over 3 h. The mixture was transferred to a 750 L
pressure filter, and the liquors were removed by application
of nitrogen pressure. To the crystallizer was charged heptane
(177 L) and toluene (120 L), and the agitator was restarted. The
wash mixture was then transferred to the pressure filter and
passed through the cake by nitrogen pressure. This displacement
wash procedure was repeated once more. The cake was then
dried by a flow of hot nitrogen (40 °C) to a constant weight and
discharged to give AZD0530 1 (81.5 kg, 100 wt/wt%, 86.7%
’
EXPERIMENTAL SECTION
Reactants and reagents were purchased from standard chemi-
cal suppliers. Quinazolone 2 was purchased from Ube Industries
(
Fine Chemicals), Ube City, Yamaguchi, Japan.
To a 1150 L hastelloy vessel equipped with a baffle and flat-
bladed turbine agitator under an atmosphere of nitrogen were
charged sequentially monofluoroanilide 7 (72.5 kg, 173.5 mols),
2
0ꢀ40 mesh sodium hydroxide (25.0 kg, 625 mol), and toluene
399 L). The agitator was started, and the vessel contents were
adjusted to 20 °C. To the mixture was then charged side chain 8
43.8 kg, 303.7 mols), followed by a line wash of toluene (73 L).
(
(
The resulting slurry was warmed to 104ꢀ106 °C over 2 h and
8
then held at this temperature for 9 h. The vessel contents were
yield), as a highly crystalline, colourless solid.
6
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Organic Process Research & Development
ARTICLE
’
COMPUTATIONAL DETAILS
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; M. A. Al-Laham, Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; ,
Pople, J. A.Gaussian 03 , Revision B.05; Gaussian, Inc.; Wallingford, CT;
All geometry optimizations and corresponding frequency
calculations were carried out at the B3LYP/6-31G* level of
theory using the Gaussian 03 suite of programs. Accurate
electronic energies were computed as B3LYP/6-31þG** single
points on the B3LYP/6-31G* geometries. Scaled zero-point
potential energies were used in the calculation of free energies,
using a scaling factor of 0.9806. Solvation energies were
obtained from single-point calculations on the gas-phase opti-
9
10
11
mized geometries, using the IEF-PCM model and the UAKS
set of radii.
’
AUTHOR INFORMATION
2
004.
Corresponding Author
(10) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502–16513.
11) Mennucci, B.; Canc ꢀe s, E.; Tomasi, J. J. Phys. Chem. B 1997,
*
To whom correspondence should be addressed. Email: steven.
raw@astrazeneca.com.
(
101, 10506–10517.
’
ACKNOWLEDGMENT
We are grateful to the AZD0530 Development Manufacturing
team at PR&D (Macclesfield) for their work in the accommoda-
tion of this process. We thank Lyn Powell and Andrew Stark for
many helpful discussions. We thank Peter Crafts for Process
Engineering support and Anna Powell for analytical assis-
tance. Finally, we are indebted to Christine Mee, Safety
Assessment, AstraZeneca, for carrying out the Ames testing
on cyanoaniline 15.
’
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