A New Approach to Rapid Parallel Development of Four Neurokinin Antagonists. Part 4. Synthesis of ZD2249 Methoxy Sulfoxide

Article abstract of DOI:10.1021/op030039z

The manufacture of ZD2249 methoxy sulfoxide (1) using a new project approach is described. Research department processes were scaled up to 100 L if process safety and robustness were not compromised; other factors were treated according to the new approach. Using this strategy, we were able to manufacture a key intermediate on sufficient scale to support delivery of 1 kg quantities of bulk drug within 6 months of the start of lab work.

Full text of DOI:10.1021/op030039z

Organic Process Research & Development 2004, 8, 33−44
A New Approach to Rapid Parallel Development of Four Neurokinin Antagonists.
Part 4. Synthesis of ZD2249 Methoxy Sulfoxide
Sharon A. Bowden, J. Nigel Burke,† Fiona Gray, Steven McKown,† Jonathan D. Moseley,* William O. Moss,
Paul M. Murray, Matthew J. Welham, and Maureen J. Young
AstraZeneca, Process Research and DeVelopment, AVlon Works, SeVern Road, Hallen, Bristol, BS10 7ZE, UK, and
Large Scale Laboratory, Macclesfield, UK
Abstract:
The manufacture of ZD2249 methoxy sulfoxide (1) using a new
project approach is described. Research department processes
were scaled up to 100 L if process safety and robustness were
not compromised; other factors were treated according to the
new approach. Using this strategy, we were able to manufacture
a key intermediate on sufficient scale to support delivery of 1
kg quantities of bulk drug within 6 months of the start of lab
substitution of the methoxy sulfoxide fragment (1). This was
analogous to the Pip sulfoxide fragment (1′) of ZD7944, a
work.
molecule with some structural similarities to the NK series,
which had previously been in development as an oral
Introduction
treatment for asthma.6
In our previous paper,1 we presented a new approach by
The incorporation of the 4-methoxy substituent required
Zeneca Pharmaceuticals to the rapid parallel development
a different synthesis from that of 1′ for the initial stages.
of several candidate drugs. An overview of the strategy was
Rather than develop a new synthesis, we had sought to apply
given and illustrated by examples taken from across the
the Research-based route wherever possible if it did not
neurokinin (NK) project.2 This was illustrated in more detail
compromise safety or robustness, as outlined in our project
by the subsequent papers concerning ZD6021 cyano acid3
strategy.1 Our route to methoxy sulfoxide (1) was based on
and the final assembly sequence.4 This contribution and the
the Research route2 and is shown in Scheme 1. Modifications
next5 describe our experiences of the manufacture of other
and manufacturing experiences are discussed below.
key fragments of molecules required for the NK programme
and further exemplify this new approach. In this case, the
specific challenges of ZD2249 methoxy sulfoxide manufac-
ture using the new project approach are discussed in detail.
Results and Discussion
Bromophenol Stage (3). The process inherited from
Research involved an apparently radical-mediated bromina-
ZD2249 was the second molecule in the NK programme
tion of 3-methoxyphenol (2) in 1,1,1-trichloroethane, driven
to enter development. The naphthalene cyano acid fragment
to completion by irradiation with a sun lamp that brought
was identical to that of ZD6021, and repeat manufacture of
the mixture to reflux. After neutralization with sodium
this portion was uneventful, as presented previously.3 The
bicarbonate, the solvent was distilled off and the crude
central (N-methylamine) portion was identical for all mol-
concentrate distilled under reduced pressure to yield the crude
ecules in the series, and the final assembly sequence has also
bromophenol (3) in 66% as a red oil. In spite of our stated
been presented in this journal recently.4 The one difference
aim of adopting Research-orientated processes for an expedi-
between ZD6021 and ZD2249 was in the 4-methoxy
tious manufacture, this stage had several undesirable features
for scale-up, which we felt could easily be removed. The
† Large Scale Laboratory, Macclesfield.
(1) Moseley, J. D.; Moss, W. O. Org. Process Res. DeV. 2003, 7, 53-57.
lack of control in a radically initiated bromination using
(2) Bernstein, P. R.; Aharony, D.; Albert, J. S.; Andisik, D.; Barthlow, H. G.;
benzoyl peroxide was a source of concern, as was the solvent,
which is banned for use in manufacture under the Montreal
Protocol.7 High-temperature vacuum distillation was also
Bialecki, R.; Davenport, T.; Dedinas, R. F.; Dembofsky, B. T.; Koether,
G.; Kosmider, B. J.; Kirkland, K.; Ohnmacht, C. J.; Potts, W.; Rumsey, W.
L.; Shen, L.; Shenvi, A.; Sherwood, S.; Stollman, D.; Russell, K. Bioorg.
Med. Chem. Lett. 2001, 11, 2769 and Albert, J. S.; Aharony, D.; Andisik,
D.; Barthlow, H.; Bernstein, P. R.; Bialecki, R. A.; Dedinas, R.; Dembofsky,
B. T.; Hill, D.; Kirkland, K.; Koether, G. M.; Kosmider, B. J.; Ohnmacht,
process did not need the radical initiator or the sun lamp
C.; Palmer, W.; Potts, W.; Rumsey, W.; Shen, L.; Shenvi, A.; Sherwood,
better avoided. Early sighting experiments showed that the
S.; Warwick, P. J.; Russell, K. J. Med. Chem. 2002, 45, 3972-3983.
(3) Moseley, J. D.; Moss, W. O.; Welham, M. J.; Ancell, C. L.; Banister, J.;
Bowden, S. A.; Norton, G.; Young, M. J. Org. Process Res. DeV. 2003, 7,
58-66.
(6) Shenvi, A. B.; Jacobs, R. T.; Miller, S. C.; Ohnmacht, C. J.; Veale, C. A.
U.S. Patent 5,589,489, 1996. Shenvi, A. B.; Aharony, D.; Brown, F. J.;
Buckner, C. K.; Campbell, J. B.; Dedinas, R. F.; Gero, T. W.; Green, R.
C.; Jacobs, R. T.; Kusner, E. J.; Miller, S. C.; Ohnmacht, C.; Palmer, W.;
Smith, R.; Steelman, G.; Ulatowski, T.; Veale, C.; Walsh, S. Abstracts of
Papers, Part 1, 214th National Meeting of the American Chemical Society,
Las Vegas, NV, Sept. 7-1, 1997; American Chemical Society: Washington,
DC, 1997; MEDI 264.
(4) Parker, J. S.; Bowden, S. A.; Firkin, C. R.; Moseley, J. D.; Murray, P. M.;
Welham, M. J.; Wisedale, R.; Young, M. J.; Moss, W. O. Org. Process
Res. DeV. 2003, 7, 67-73.
(5) Parker, J. S.; Smith, N. A.; Welham, M. J.; Moss, W. O. Org. Process Res.
DeV. 2004, 8, 45-50.
10.1021/op030039z CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/05/2003
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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Scheme 1
Table 1. FED parameters for bromophenol stage
and could in fact be run in the more acceptable dichlo-
romethane at 20 °C with the exotherm controlled by the
bromine addition rate. The distillation was avoided by
successful telescope into the following crystalline O-thio-
carbamate stage, as discussed below.
parameter
low level
high level
bromine charge (equiv)
dichloromethane charge (volumes)
addition temperature (°C)
addition time (min)
0.75
6
5
15
5
0.95
8
20
60
20
reaction temperature (°C)
investigated with their high and low levels are shown in
Table 1; however, the fast addition rate and low-temperature
combinations were deliberately excluded from the design as
being unsuitable. The FED showed that longer addition times
moderately favoured better selectivity, whilst other factors
had little effect. Thus, we chose the lower temperature to
control the exothermic addition, and 0.85 equiv of bromine
as a compromise between unreacted 2 and dibromide (12).
However, larger scale trials showed that the lower charge
of bromine at 0.75 equiv with stirring at room temperature
for several hours gave a moderately improved solution yield
of 3. No other work specific to this stage was undertaken as
it was successfully telescoped into the O-thiocarbamate stage.
O-Thiocarbamate Stage (4). The Research process
redissolved the distilled bromophenol (3) in DMF to which
DABCO and dimethylthiocarbamoyl chloride (DMTCC)
were added sequentially in portions, to acylate the free
phenol. After an overnight hold, the crude O-thiocarbamate
was precipitated by the addition of a large volume of water
(25 volumes), and the crude dried solid then recrystallised
from hot methanol in 44% overall yield for the two stages.
We were concerned about the potential toxicity of DMTCC
by comparison with the O-analogue, dimethyl carbamoyl
chloride, a known animal carcinogen12 generated at low
levels during the preparation of other NK compounds.1,4 The
advice from our occupational health department was that the
risk from the nonvolatile S-analogue was much lower and
could be used under standard precautions for lab work and
Large Scale Lab (LSL)13 manufacture.
The main challenge of this bromination process was to
control the ratio of the desired bromophenol (3) to the
dibromide (12) (and other multiple bromination products),
whilst achieving adequate conversion of 2. The Research
conditions gave a 12:1 ratio in favour of the product with
some residual 2 (which is an oil and is lost in the mother
liquors at the next stage). Our change to dichloromethane
gave a slightly worse but still acceptable ratio.8 We briefly
investigated alternative conditions (standard electrophilic
bromination,9 NBS in acetonitrile,10 and NBS in aqueous
base11), but all gave much higher levels of regioisomeric di-
and tribrominated products as determined by LC-MS.
To establish that we were working in a robust region of
reaction space,1 and possibly to optimize the reaction further,
particularly the ratio, we conducted a factorial experimental
design (FED) using a four-cell HEL Automate reactor. We
investigated five parameters at two levels in eight experi-
ments, resulting in a quarter factorial. The parameters
(7) Under Article 2E of the Montreal Protocol (United Nations Environment
Programme, 1988), production and use of 1,1,1-trichloroethane, which is
an ozone-depleting chemical, should have been phased out in developed
countries by 1996.
(8) We also tried chloroform which gave a marginally better ratio than that
with dichloromethane, but not sufficiently so in our view to justify its usage.
(9) Sandin, R. B.; McKee, R. A. In Organic Syntheses; Blatt, A. H., Ed.; John
Wiley and Sons: New York, 1943; Collect. Vol. 2; pp 100-101.
(10) Carreno, M. C.; Garcia Ruano, J. L.; Sanz, G.; Toledo, M. A.; Urbano, A.
J. Org. Chem. 1995, 60, 5328.
(11) Auerbach, J.; Weissman, S. A.; Blacklock, T. J.; Angeles, M. R.; Hoogsteen,
K. Tetrahedron Lett. 1993, 34, 931.
(12) Irving Sax, N. Dangerous Properties of Industrial Materials, 5th ed.; Van
Nostrand Reinhold Company: New York, 1979.
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We had few other concerns with this stage but felt that
several worthwhile improvements could quickly be assessed.
The first of these was to prove the reaction could be
performed in dichloromethane, which allowed us to telescope
from the previous stage, hence avoiding the distillation of
the bromophenol. We cut down the equivalents of both
DABCO (2.4 to 1.25) and DMTCC (2.4 to 1.03) without
compromising the result. DMTCC also had much higher
solubility in dichloromethane and so could be added as a
solution, thus avoiding solid charging of a key reagent. A
change to triethylamine from DABCO gave a gelatinous
precipitate (presumably Et3N‚HCl) so that we retained the
more efficient DABCO. An attempt to avoid the aqueous
wash with dilute HCl to remove DABCO‚2HCl (now
possible with dichloromethane in place of DMF) led to the
precipitation of a white solid during subsequent processing
and low-strength product, presumably both due to the
presence of DABCO‚2HCl. The reaction was notably faster
in DMF compared to dichloromethane (4 h versus 18 h at
20 °C), but the product form was poor and required drying
before recrystallisation. Using NMP as a cosolvent (7% v/v
with dichloromethane) did not improve the reaction rate and
resulted in high losses to liquors. Finally, a solvent swap
after the aqueous wash into methanol and distillation of the
dichloromethane was successful, which avoided isolation and
drying of the crude O-thiocarbamate. The product crystallized
well from methanol, as noted by our Research colleagues,
but was often slow to initiate. Seeding or self-seeding at ∼30
°C proved to be robust in the lab, and during manufacture
only the first batch required seeding, the second two
crystallising spontaneously.
Three batches were manufactured in the LSL. Quality was
typically >96% with the dibromo analogue (13) being the
major impurity (untypically higher in the last batch). High
product strengths indicated that UV-invisible inorganic and
DABCO‚2HCl residues had been successfully removed. DSC
analysis of the product 4 showed that there was no thermal
instability at operational temperatures, and no further hazard
testing was judged necessary in this case. The overall yield
was ∼45%, effectively the same as the Research process
but with simplified operations; about 15% product remained
in the liquors which could not be isolated.
Overall, we were able to apply standard process develop-
ment improvements to these two stages and combine them
into one telescope. Although the yield was moderate, we
were able to produce adequate quantities of material in three
batches. The processes had proved both safe and robust in
manufacture and so had met the project remit, and further
improvements were passed over in favour of working on
later, more challenging stages as discussed below.
S-Thiocarbamate Stage (5). This stage provided the first
real test of applying the Research chemistry approach to this
target molecule, as mentioned in our introductory paper.1
Formation of the S-thiocarbamate is achieved from the
O-thiocarbamate precursor by a Newman-Kwart rearrange-
ment14 using the method of T´ıma´r15 in refluxing N,N-
diethylaniline (bp 218 °C). This could only be achieved in
the LSL in a heating mantle, and that limited it to 20 L
maximum. Previously for ZD6021 we had decided not to
use a heating mantle for the cyano ester stage, although in
part this was due to the presence of cyanide.3 That reaction
had ideally required 180 °C, but only 130 °C could be
achieved in a jacketed vessel, attenuating reaction times from
4 to 48 h. Necessity forced a rethink for the S-thiocarbamate
process for which the higher temperature was essential.
Fortunately, the process received from Research was also
very concentrated, so that the manufacture could be comfort-
ably completed in the 20-L flask in three batches, one of
which was a smaller-scale proving batch.
The Research process heated the O-thiocarbamate in
degassed diethylaniline at reflux for 3-4 h; the solvent was
distilled off by short-path distillation, and the residue was
precipitated in ice-cold 6 M HCl, extracted with diethyl ether,
dried, and concentrated to a brown solid which was recrys-
tallised as a white solid from methanol in ∼60% overall
yield. Aside from the operational use of the heating mantle
which was new to the LSL at the time, we were concerned
about the need for degassing the reaction solution, and its
effectiveness in the LSL versus the lab. Lab preparations
showed that degassing to remove oxygen was indeed
necessary; without it, a lower yield of sticky-brown product
higher in impurities resulted. Both evacuation/purging and
sparging techniques were shown to be acceptable in the lab.
In the LSL both methods were used in combination and were
found to be successful without issue. If the impurity profile
was good, it was found that a straightforward drown-out of
the reaction mixture directly into an excess of ice-cold 6 M
HCl could be used in place of the extractive procedure. This
yielded the S-thiocarbamate as a light-brown solid which was
washed with water and dried. Typical lab yields had been
around 60% as for the Research process. In fact, the
combined yield in the LSL for the 3 batches was 88%, well
above the planning yield of 59%. Quality was also good,
being typically 96% by LC area and >95% by strength. The
major impurities were residual starting material (4), dibromo-
O-thiocarbamate (13), des-bromo-S-thiocarbamate (14), and
dibromo-S-thiocarbamate (15), of which 4 and 15 were the
two major ones (up to 3%, but only one predominated). Batch
three had an untypically high level of 15 at 9.3%; all other
impurities were below 1% by HPLC.
Finally, preliminary hazard work of a DSC on the product
5 revealed a possible concern from 181 °C, well below the
proposed reaction temperature. A more thorough, larger-scale
Carius tube test revealed a prolonged double exotherm from
228 °C, quite possibly the heat of reaction since this is close
to the temperature of the rearrangement. Although this was
(13) The Macclesfield LSL is a cGMP manufacturing facility for synthesis of
bulk drug for clinical studies and uses all glass vessels. It is typically where
the first significant scale-up of a process occurs, and commonly delivers
tens of kilograms of intermediates and kilograms of bulk drug. It consists
of a range of glass reactors 10-100 L in scale, fully contained with other
ancillary equipment in fume cupboards. Operating ranges vary from -78
to +130 °C. Atmospheric hydrogenations can be performed, and a 20-L
rotary evaporator is available for distillations if required. Product is generally
isolated as a solid on Nutsches. AstraZeneca has several other LSLs at
different sites which operate in a similar fashion.
(14) Newman, S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980 and Kwart, H.;
Evans, E. R. J. Org. Chem. 1966, 31, 410.
(15) Sebo¨k, P.; T´ıma´r, T.; Eszenyi, T.; Patonay, T. Synthesis 1994, 837.
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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with CBz piperidone (7), by analogy with the nearly identical
Grignard coupling of ZD7944 bromosulfide (6′) with CBz
piperidone.6 Using 1.35 equiv of 6 in 1:1 toluene:THF gave
a poor conversion of 6 to CBz alcohol (8) in only 30% yield
after chromatography after several attempts. As noted in our
introductory report,1 we used Kepner-Tregoe analysis for
problem solving at critical points, and this proved to be
effective here. Several potential causes for the low yield were
proposed, but most were readily eliminated as being incon-
sistent with other experimental data. As discussed above, it
was quickly shown by this methodical approach that residual
solvent (methanol) in bromosulfide (6) was the cause of the
problem (by partially quenching out the Grignard reagent).
Azeotroping 6 with toluene removed the residual methanol,
improving the yields significantly in the subsequent reaction.
Whilst investigations had quickly been proving this
hypothesis, we had also tried the harsher direct lithiation of
bromosulfide with butyllithium at -78 °C, which appeared
to work better. With the toluene-azeotroped bromosulfide,
the lithiation reaction was quickly optimized in the lab. Neat
anhydrous THF was found to be better than the toluene-
THF mixtures we had started with. Using a 1.2 equiv excess
of 6, a 65-70% yield of 8 could be obtained after
chromatography. These lithiation conditions were used for
the first batch in the LSL, but unfortunately a troublesome
unknown impurity was produced in this batch at 15% which
had previously only been seen at <5% in lab work. Because
of the concern that this had not scaled up well, we reverted
to the more well-known (in our hands) Grignard conditions.
With the other improvements and changes now made, the
next three batches all performed well under the Grignard
conditions, to give the crude product after workup as a
viscous brown/red oil.
judged acceptable on the 20-L scale, additional hazard testing
would have been required for further scale-up. Fortunately,
this did not present us with a capacity issue due to the
concentrated nature of the process.
Bromosulfide Stage (6). This stage was inherited as a
partial telescope from Research and was already relatively
simple. Hydrolysis of the S-thiocarbamate in methanol with
7.6 equiv of KOH gave the intermediate thiol (16) as an oil
after an acidic workup, which was redissolved in DMF and
treated with K2CO3 and methyl iodide to give the desired
bromosulfide. The quantity of base seemed excessive, and
this was readily reduced to 2.2 equiv, whilst the methyl
iodide charge was cut down from 1.7 to 1.1 equiv (1.0 being
just insufficient). The solvent swap to DMF also seemed
unnecessary, so that the alkylation reaction was also con-
ducted successfully in methanol. On completion, water was
added and the product extracted into MTBE and concentrated
to an oil. Hazard studies (Carius tube) showed that, although
the hydrolysis phase was essentially an “all-in” process, there
were no exotherms of concern; the alkylation reaction was
effectively under process control by the methyl iodide
addition.
This process was developed for manufacture in only 2
weeks, well inside our 4-6 week target. Other than the
changes noted above, dimethyl sulfate was investigated as
an alternative alkylating agent. However, methyl iodide gave
a slightly faster, cleaner reaction so that this was retained,
other safety and health issues being considered well con-
trolled in the LSL environment. Quality was as good (>98%
by HPLC), except for that of batch three where the high
level of dibromo-(S)-thiocarbamate carried through as the
dibromosulfide (17) at 6% by HPLC. Crude yield of the
concentrated oil for each of the three batches was >100%,
but with quality so high, we assumed this was residual
MTBE. The product was an oil, and we had no initial
standard with which to compare it. Unfortunately, the first
batch of the following Grignard reaction was partially
quenched, and we assumed from this that the residual solvent
was, in fact, methanol. Azeotroping the bromosulfide batches
from toluene under vacuum distillation reduced the yield to
a more plausible 90% each and allowed the CBz alcohol
stage to proceed smoothly. Our rapid development had been
too rapid in this case.
Chromatography was required to remove the residual
quenched Grignard reagent product methoxy sulfide (18),
which always contaminated the product due to the excess
of 6 used. Yields were much poorer without an excess of
∼1.2-1.3 equiv of 6, and this was the best compromise.
Residual CBz piperidone (7) was a lesser contaminant which
was also removed by chromatography, although in this case
crystallization could also be effective. For the LSL, a loading
of 14:1 silica gel:crude CBz alcohol was used on a Nutsche
filter, eluting with ethyl acetate/hexane combinations. This
performed well in the LSL, giving product of 80-85% by
NMR strength. A further crystallization/trituration in 3
volumes of ethyl acetate/hexane gave an overall yield of 75%
for the two purification steps of 8 with 100% strength. After
the first few pure column fractions had been concentrated
to dryness, further purifications were found to be unneces-
sary, as the pure fractions seeded the new liquors on standing.
This also avoided the need to concentrate all the liquors,
saving considerable time.
CBz Alcohol Stage (8). This stage proved to be the most
demanding test of the new strategy on scale-up, since
purification by chromatography was required. Initially,
Grignard conditions were used in coupling bromosulfide (6)
Neither process (lithiation or Grignard) was formally
hazard-assessed in this case, as they were deemed to be
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Scheme 2
similar to the analogous ZD7944 stage which had been fully
assessed previously. The lithiation was run at -78 °C which
was judged low enough to control any potential exothermic
addition. The Grignard reaction was initiated by a small
charge of bromosulfide (6) (12% maximum) and controlled
by dropwise addition over several hours only after the initial
exotherm had subsided, keeping the temperature below 30
°C at all times. This worked well for all three batches.
Overall, a yield of 60-65% for the three Grignard batches
was achieved, with quality in the range 96-99%, the only
significant impurity being residual 7 at <0.5%, with the mass
balance being accounted for by solvent. Output was of
necessity very poor, due to the large volumes of solvent
required for the chromatography. This also took 3-4 weeks
just for the purification alone. However, accommodating a
lithiation and then a Grignard reaction, with chromatographic
purification of an intermediate halfway through a synthesis,
were within the new project remit and were judged a success.
CBz Sulfide Stage (9). This was another process that was
used without major changes direct from Research. The
alcohol is activated as the TFA ester (19) and this is displaced
by hydride transfer from triethylsilane (TES) to give the
desired reduced product, CBz sulfide (9). Some of the
elimination product, CBz alkene (20) is also formed as an
impurity. A further competing reaction is deprotection of the
CBz group to give piperidine (21).
agitation and addition rate were not well controlled on the
small scale (we were very short of material for lab work at
this point in the sequence, and the solvent-free system was
of necessity highly concentrated). We decided to investigate
the effect of fast and slow TFA additions rates. The fast
addition (<5 min) gave low levels of the alkene (∼1%), but
the exotherm was uncontrolled. The slow addition gave a
relatively high level of alkene to product, whilst unreacted
8 was still present during the first hour, but the level of alkene
did not increase during the second hour of the addition. Given
the three phases we had already observed, we suspected the
solubility characteristics of the reaction were changing and
thus affecting the reaction kinetics. We also tried addition
of TES to the other two components, but formation of alkene
predominated in all these cases. From this we deduced that
addition of 8 to a rapidly stirred solution of TFA and TES
should give us the best outcome. Since we could not use
solvent, 8 had to be added in portions to these reagents. Some
alkene was observed after the first portion, but this was found
not to increase with subsequent portions, and the level by
the end of the reaction was acceptably low. This procedure
was adopted for the LSL, and after a somewhat tedious
workup, the product CBz sulfide could be isolated after
crystallization of the crude oil from ethyl acetate/hexane as
a white solid in typically 70% yield for three batches. Final
quality was 99% with any residual CBz alkene removed by
the crystallization; isohexane washes were needed to remove
siloxane byproducts resulting from the bicarbonate quench
of excess TES. This was another stage that had less than 4
weeks’ development time spent on it; it was also severely
hampered by lack of starting material 8, due to problems
with the previous stage and from being several steps into a
lengthy synthesis.
Alternative Hydrogenation Process. An alternative two-
step hydrogenation process was also briefly investigated for
the CBz sulfide stage, based on a similar approach used for
the analogous ZD7944 stage (Scheme 2). Dehydration of
alcohol 8 with catalytic 10 mol % methane sulfonic acid in
toluene under Dean-Stark conditions proceeded very quickly
(<1 h) and cleanly to give CBz alkene in effectively
quantitative yield. Reduction of the trisubstituted alkene with
Wilkinson’s catalysts proved less facile, however. There was
very little reaction at room temperature and pressure with 5
mol % catalyst, although at 60 °C with this loading, a lab
sample of 9 contaminated with 20% alkene was usefully
converted cleanly to the desired product. This procedure had
worked well for ZD7944, but there was not time to develop
it further for ZD2249 CBz sulfide since fortunately, the TFA/
TES procedure was successful before further study was
required (e.g., higher H2 pressures, lower catalyst loadings).
The Research method had used 2.0 equiv of both TFA
and TES. A similar reaction for ZD7944 had used 10.0 equiv
of each, and on discussion with Research, it transpired that
their yields had been highly variable without obvious
explanation. On scaling up to several grams (without solvent),
we observed three phases using this combination (assumed
to be TFA, TES, and substrate); thus, it is possible that
uneven agitation may have accounted for some of these
differences. We investigated solvents to overcome this
potential problem and found that both dichloromethane and
isohexane gave good selectivity for 9 over alkene (20) (∼50:
1). Unfortunately, whilst the ratio between these components
was good, there was also extensive degradation in addition.
Other solvents tried (toluene, ethyl acetate, and NMP) all
gave the alkene as the major product. We therefore perse-
vered with the solvent-free reaction. Reducing the temper-
ature to -10 °C also improved the selectivity for formation
of 9 over alkene formation or CBz deprotection. However,
lower temperatures led to higher levels of the postulated
intermediate TFA ester (19), which in turn led to higher
levels of alkene again.
Given these problems, we attempted an FED to investigate
other possible factors, but the results were not reproducible
when scaled up. We suspected that physical factors such as
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CBz Sulfoxide Stage (10). Kepner-Tregoe potential
problem analysis had identified this stage as potentially one
of the more technically challenging ones due to the asym-
metric oxidation of the sulfide to the (S)-sulfoxide. The
Research process took place at -30 °C over a period of 6
days, which was deemed to be unacceptably long. Again, a
previous process had been developed for ZD7944 CBz
sulfoxide (10′), and this was found to be suitable for
manufacture in this case with only minor modifications.
The key aspect of this reaction was in achieving a high
enantiomeric excess (ee). Factors affecting the ee were
known from the literature,16 the related ZD7944 process and
the ZD3638 project, which included an extensively studied
asymmetric sulfoxidation reaction.17 The literature indicates
that a 2:1:1:1 ratio of diethyl tartrate (DET):Ti(O-iPr)4:
sulfide:water gives the optimum ee. An FED performed on
ZD7944 CBz sulfide had shown that a range of 0.5-1.5
equiv of water was ideal. Reliable water analysis was critical,
but unfortunately it was found that CBz sulfide was not
compatible with the Karl Fischer reagent. We therefore had
to assume the CBz sulfide was dry and analysed the water
content of the DET/dichloromethane solution, assuming that
the solvent would be the biggest source of moisture. The
critical water charge could then be made up to 1.0 equiv on
the basis of this result.
The temperature was also known to be critical. In this
case, oxidation at -5 °C gave product with an ee of 85%;
decreasing it to -15 °C improved the ee to 94%, which was
judged to be an acceptable compromise between reaction
rate and ee. The addition of the cumeme hydroperoxide (used
as the oxidant) was exothermic, which also affected the ee.
The addition rate had to be adjusted to so that the internal
temperature of the vessel could be controlled, since any
increase would erode the final ee of the product. The cumene
hydroperoxide charge was also studied. The reaction was
completed overnight at -15 °C with a slight excess (1.05
equiv) of hydroperoxide, with only 1.3% of the sulfone (22)
being formed. On using 1.2 equiv of hydroperoxide, the
reaction could be completed in just 2 h, but the level of this
impurity rose significantly. The overnight hold with the lower
charge was therefore preferred.
or hexaethyldisiloxane (from quenched TES) was present.
It was assumed the DET residues were enough to hinder the
crystallization. Refluxing the product-containing dichlo-
romethane solution with NaOH in the presence of n-Bu4NOH
removed the DET residues to <0.1% by GC determination;
without the n-Bu4NOH, the procedure was less successful,
and although beneficial, an oil still resulted. However, since
the DET did not cause a problem with the following stages
and given the proximity of the manufacturing deadline, we
decided not to introduce a new reagent with unknown
consequences for the impurity profile so late in the develop-
ment process. CBz sulfoxide was therefore concentrated to
a viscous yellow oil of 60-70% strength against an analyti-
cally pure standard, giving a corrected yield of 70-85%.
The following methoxy sulfoxide stage was an apparently
simple hydrolysis of the CBz carbamate group with KOH.
We therefore attempted to combine the previous alkaline
hydrolysis of the CBz sulfoxide stage (during its workup)
with this reaction hydrolysis step. However, these attempts
were unsuccessful in the time available. Product-related
quality was typically 96% by LC (i.e. allowing for solvents
and DET residues), with 1.3% of the sulfone (22) and no
residual CBz sulfide. Sulfated ash analysis showed <0.1%
inorganic residues, indicating that the titanium oxide/salts
had been successfully removed. The ee was determined by
chiral LC and was consistently around 94%, which was
satisfactory, given known improvements in quality in later
steps. Unfortunately, both the CBz sulfone (22) and the
unsaturated sulfoxide (23) coeluted with the required (S)-
enantiomer of 10, which made accurate determinations of
ee difficult. A good assessment of these impurities from
achiral LC was required to generate useful results. No formal
hazard assessment was conducted in this case, again because
of the close similarity with the previous ZD7944 process.
Overall, two batches were successfully manufactured, the
first a smaller proving trial, with 88% overall yield and
94.4% ee in both cases. Manufacture was surprisingly
trouble-free, which we attributed to good understanding of
this type of process from previous projects.
Methoxy Sulfoxide Stage (1). The last stage in the
synthesis of this fragment of ZD2249 proved to be the most
problematic, although chemically one of the simplest. It was
again a stage for which the development was severely
curtailed by lack of starting material, which of necessity
reduced the development time and compressed it to a few
weeks just before the planned manufacture. Once again,
experience from a related ZD7944 stage, Pip sulfoxide (1′),
formed the basis of the process and undoubtedly saved some
time. Using 10 equiv of KOH in industrial methylated spirits
(IMS) required a total of 6 h compared to only 3 for ZD7944;
increasing the KOH charge to 14 equiv halved the reaction
time, but other impurities started to become significant. The
reaction was known to proceed partly via the intermediate
ethyl carbamate (24) (formed by partial solvent hydrolysis),
which seemed unusually stable in this case, and required
prolonged heating with an increase in reaction times for
completion.
The workup for this reaction required treatment of the
reaction mixture with HCl to dissolve the insoluble titanium
oxide residues. However, the product would not crystallize
(the Research generated sample was a solid); GC showed
the presence of DET residues, but neither cumene alcohol
(16) For reviews, see: Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987,
43, 5135-5144 and Kagan, H. B. Asymmetric Oxidation of Sulphides. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993;
pp 203-226.
(17) Hogan, P. J.; Hopes, P. A.; Moss, W. O.; Robinson, G. E.; Patel, I. Org.
Process Res. DeV. 2002, 6, 225-229.
38
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Vol. 8, No. 1, 2004 / Organic Process Research & Development

was therefore required at the methoxy sulfide stage. Our
Research colleagues had recrystallised 1 with tartaric acid
to improve the ee. This was a step we had been hoping to
avoid, but although we did not need to improve the ee, we
found this procedure, when modified, to be effective at
removing dimeric impurity (27). The Research procedure had
sacrificed yield for homochiral quality; when we reduced
the ethanol solvent for the crystallization from 13.5 volumes
down to just 3.5 volumes, we achieved a 55% yield. This
was a good result as it was estimated that there was only
66% methoxy sulfoxide present by mass in the sample. The
free base of 1 was then obtained by treatment of the tartrate
salt 11 with aqueous NaOH and extraction into hot toluene
at 80 °C. In the LSL the tartrate salt failed to crystallize
from 3.5 volumes of ethanol, but on increasing the volume
to 5.5 and adding a seed of tartrate salt, the product
precipitated as required. Attempts to completely re-extract
the purified methoxy sulfoxide into toluene from an aqueous
NaOH solution were however unsuccessful. Ethyl and butyl
acetates were also unsuccessfully examined as extraction
solvents. Fortunately, and somewhat surprisingly, it was
found that the aqueous solution of 1 could be used directly
in the reductive amination step that followed. This concluded
the manufacture of ZD2249 methoxy sulfoxide.19
Final Assembly Stages of ZD2249. The coupling of
ZD6021 cyano acid with ZD6021 N-methylamine was
achieved with EDCI to give the amide alcohol (28) which
was oxidized to the amide aldehyde (29) by Swern oxidation
and used without isolation as described previously.4 The
reductive amination conditions of coupling aldehyde (29)
with methoxy sulfoxide (1) to give crude ZD2249 are worth
a separate comment, however, as they were untypical of the
standard conditions used for the other compounds in the NK
series.
An acid-base extraction procedure as for ZD7944 was
then used for the purification and isolation, which gave a
dichloromethane solution of the product which was concen-
trated to an oil. This procedure appeared satisfactory, but
the final crystallization solvent combination of toluene/
isohexane was less than ideal, with the product often oiling
out and recovery being disappointing despite ∼95% observed
solution yields. A range of alternative solvents was rapidly
screened, but none of these offered any significant advantage.
A 3:1 isohexane:toluene solvent ratio was used to improve
recovery (to about 70% yield with 88% strength), although
the physical form remained poor. Unreacted 10 and carbam-
ate 24 remained in the neutral toluene phase during the
aqueous extractions. The deprotected sulfide 25 was seen,
but at <0.1%, whilst the deprotected sulfone 26 was seen at
up to 5% in reaction liquors. This was puzzling as no more
than 1.5% was carried through from 10, which indicated that
the oxidation was occurring during the hydrolysis, more so
with the higher equivalents of KOH. Fortunately the crystal-
lization reduced this impurity to <1% in the isolated product.
No other work could be undertaken in the time, and so
methoxy sulfoxide was manufactured in the LSL in a single
batch in unexpectedly high yield of 99%, corrected for
strength as determined by LC of 89%. Unfortunately, NMR
analysis showed that it contained 20 mol % of a dimeric
compound (i.e., 40% w/w). The impurity could not be
detected by LC (or it coeluted with the product peak) despite
much effort, but NMR analysis (1H and 13C experiments)
tentatively assigned the structure as the methylene-bridged
dimer (27). An analogous impurity had been assigned from
the equivalent ZD7944 stage, albeit at only a 5% level. The
assumption in both cases was that a prolonged hold, possibly
exacerbated by heating during the distillation of the dichlo-
romethane solution, in the presence of basic residues (NaOH)
had effected double substitution by the piperidine NH group
on dichloromethane to result in the methylene-bridged dimer
(27), a not uncommon occurrence when using this solvent.18
The amide aldehyde (29) was used as a dichloromethane
solution, which had already been successfully telescoped
from the Swern oxidation directly into the coupling stage
for ZD6021, using borane-pyridine complex as the reducing
agent in the presence of methoxy sulfoxide (1). Early lab
samples of 1 were relatively free of dimeric impurity (27).
Identification in later samples of ZD2249 Crude was delayed
because this impurity coeluted with an expected monochloro
impurity (derived from dehalogenation), which was assumed
to be the major problem. At 30 °C, 0.5 equiv of BH3 had
been sufficient to drive the reaction to completion; however,
once 27 was identified, it was noted that 27 also increased
in this reaction with temperature. A lower temperature with
1.0 equiv of BH3 were required to complete the reaction.
Attempts to use this contaminated material directly in the
next stage (reductive amination coupling to the amidealcohol
via the aldehyde) on the assumption that the proposed dimer
should be inert in this reaction were unsuccessful. The dimer
gave rise to another impurity at ∼20% in this penultimate
stage which could not be removed. A re-treatment procedure
(18) Lee, S. A.; Robinson, G. E. Process DeVelopment: Fine Chemicals from
Grams to Kilograms; Oxford University Press: Oxford, 1995.
(19) Several other potentially shorter routes to methoxy sulfoxide that were briefly
investigated may also be reported at a later date.
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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39

An acidic quench followed by base and brine washes
removed other impurities and gave crude ZD2249 in ∼80%
strength, if the dimer was not present in 1.
also used to purify 7.5 kg of CBz alcohol which it was not
possible to purify any other way.
If the safety and health issues were less for ZD2249
compared to ZD6021, the quality issues were much greater
and required additional attention. Fortunately, we had learnt
from experience that greater analytical support was required,
which was especially useful in identifying impurities and
for developing more demanding chiral LC methods. More
analytical resource was made available for this project, and
this is reflected in the acknowledgments.
We attempted to address the material supply issue by
removing 100-g samples from the manufacturing supply at
key stages to facilitate later lab work (these quantities had
been included in the materials plan). Unfortunately, stages
4 and 8 were chosen, and these were the two with the most
significant manufacturing issues; therefore, this strategy was
only partially successful. This remains an issue in any long
synthesis that is developed at a fast rate.
The FED approach was again used extensively on this
project, maximizing learning from a small number of small-
scale reactions. Kepner-Tregoe techniques were also ap-
plied, not just to problem-solving and decision-making, but
also for potential problem analysis, which was conducted
right at the start of this project, having learnt from experience
on ZD6021.
Overall, against our target rate of developing each stage
in 4 weeks, we found that ZD2249 had taken slightly longer,
although the majority of stages were developed in 5 weeks,
with the average being 6 weeks. A couple of stages took
significantly longer. As with ZD6021, safety and robustness
had been the key factors, although quality had also required
some effort. Other factors such as environment, health,
operability, output, and yield had received some attention,
but no work was driven by cost at this early stage (although
raw materials were generally cheap, 10 equiv of TES and
TFA would not be acceptable for a manufacturing process!).
ZD2249 manufacture proved to be probably the most
challenging example of the four compounds undertaken on
this new project strategy, certainly from a delivery point of
view if not from a technical one, and this was almost entirely
due to the difficulties of the methoxy sulfoxide fragment
manufacture. Even so, we delivered the desired quality of
bulk drug within the demanding 6-7 month deadline,
although the delivery was slightly down on the target mainly
due to the quality issues at the methoxy sulfoxide stage. That
we were able to manufacture ZD2249 without any hazard
incident and with only one intermediate batch out of 20
batches manufactured20 being unsuitable for use, again
supports the conclusion that this new project approach was
both safe and robust.
Since the dimer 27 was present in the manufactured batch
of 1, a recrystallisation as the tartrate salt (11) was developed
to remove it, as discussed above. The tartrate salt was then
neutralized with NaOH, and in the lab, 1 had been re-
extracted into toluene. In the LSL, this was only moderately
successful, with most of 1 remaining in the aqueous phase.
It was decided to attempt a two-phase reductive amination
using the aqueous phase containing 1 diluted with methanol
and the dichloromethane solution of 29. (Dichloromethane
did not give rise to the dimer 27 under these reaction
conditions.) These solutions were stirred together for 2 h
before adding 1.0-1.2 equiv of BH3 and leaving to stir
overnight. Despite the potential for quenching the BH3
reagent with water (water sensitivity had been shown for
ZD6021),4 a good conversion to ZD2249 crude was achieved,
and the impurity profile was even improved compared to
the mono-phasic reaction. Two batches were prepared in the
LSL in 79% yield, the second larger batch using 1.2 equiv
of 29 as this was the material available in greater excess at
the time. Quality was moderate at only 75%, with amide
alcohol (28) the major impurity at 10.5%, but this was readily
removed on forming the ZD2249 hydrogen fumarate salt.
Overall, this was a highly pleasing result; the use of a
two-phase reductive amination with an apparently water-
sensitive reagent was a significant and surprising bonus at
this phase of the project. The hazard issues were not
considered serious in this case, since a full assessment had
already been performed for the ZD6021 crude stage using
similar methodology. The resulting final quality of ZD2249
hydrogen fumarate salt was 94.8%, which was just on the
acceptable limit we had set ourselves. The final yield of 0.95
kg was somewhat down on the planned 1.3 kg, but was still
sufficient to support the required clinical trials.
Conclusions
ZD2249 methoxy sulfoxide manufacture provided another
good exemplification of our new project strategy,1 in
particular, our revised approach to traditional long-term
manufacturing factors. Chemical safety remained our first
concern, and early discussions with the Process Hazards
Section once again proved beneficial. Hazards work was less
than for ZD6021 cyano acid,3 in part because the chemistry
was judged less hazardous, but we were undoubtedly
fortunate that several similar transformations had been fully
hazard assessed for pilot-plant manufacture for ZD7944.
Health hazards were also generally lower than for ZD6021
cyano acid.
We also repeated our aim of demonstrating that Research-
type processes could successfully be operated on up to 100-L
scale with minimal developments to deliver 1 kg of bulk
drug. This included the high-temperature Newman-Kwart
rearrangement (S-thiocarbamate) where high temperatures
had not been possible previously,1,3 the Grignard/lithiation
reaction (CBz alcohol), and the Kagan asymmetric oxidation
reaction (CBz sulfoxide). Large-scale chromatography was
Experimental Section
General Procedures. Reaction mixtures and products
were analysed by reverse phase HPLC on Hewlett-Packard
1050 or 1100 instruments according to the following condi-
(20) Manufacture of the methoxy sulfoxide portion required 20 batches in total,
being generally three batches per stage for the early stages and one to two
for the later ones. No batches were lost from either repeat manufactures of
the cyano acid or N-methylamine portions.
40
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Vol. 8, No. 1, 2004 / Organic Process Research & Development

tions. Method A (general): column, Waters Spherisorb S5
ODS-2, 250 mm × 4.6 mm i.d.; eluent, 550:450 acetonitrile:
water with 0.1% v/v TFA; flow rate 1.0 mL/min; wavelength
230 nm; injection volume 5-10 µL. Typical retention times
were the following: methoxyphenol (2) 3.7; bromophenol
(3) 5.1; O-thiocarbamate (4) 11.2; dibromo-O-thiocarbamate
(13) 18.8; S-thiocarbamate (5) 9.2; bromosulfide (6) 9.9; CBz
piperidone (7) 3.8; CBz alcohol (8) 7.9; methoxy sulfide (18)
7.0; CBz sulfide (9) 37.0; CBz alkene (20) 34.0; CBz
sulfoxide (10) 7.8; DET 2.7; CBz sulfone (22) 10.5; methoxy
sulfoxide (1) 3.1 min. Method B (general): column, Waters
Spherisorb S5 ODS-1, 250 mm × 4.6 mm i.d.; eluent, 550:
450 acetonitrile:water with 0.1% v/v TFA; flow rate 1.5 mL/
min; wavelength 230 nm; injection volume 5 µL. Typical
retention times were the following: S-thiocarbamate (5) 7.0;
bromothiol (16) 8.3; bromosulfide (6) 9.4; CBz piperidone
(7) 3.6; CBz alcohol (8) 8.8; CBz alkene (20) 20.2; CBz
sulfide (9) 21.7 min. Method C (determination of ee):
column, Chiralpak AD, 250 mm × 4.6 mm i.d.; eluent, 80:
20 hexane:absolute ethanol; flow rate 1.0 mL/min; wave-
length 230 nm; injection volume 10 µL. Typical retention
times were: CBz sulfide (9) 14.6, (R)-CBz sulfoxide (R-
10) 27.1, (S)-CBz sulfoxide (10) 31.5 min. Method D
(determination of ee): column, Chiral CBH, 150 mm × 4.0
mm i.d.; eluent, 10:90 2-propanol:aqueous buffer (0.013 M
aqueous KH2PO4 adjusted to pH 7 with KOH); flow rate
1.2 mL/min; wavelength 220 nm; injection volume 10 µL.
Typical retention times were the following: (R)-methoxy
sulfoxide (R-1) 5.4; (S)-methoxy sulfoxide (1) 13.3 min.
HPLC purities/strengths are area % normalized, except where
noted otherwise. Melting points were determined using a
Griffin melting point apparatus (aluminium heating block)
and are uncorrected. 1H and 13C NMR spectra were recorded
on a Varian Inova 400 spectrometer at 400 and 100.6 MHz
respectively with chemical shifts given in ppm relative to
TMS at δ ) 0. Electrospray (ES+) mass spectra were
determined on a Micromass LCT with time-of-flight and
electron impact (EI+) mass spectra were determined on a
Micromass Autospec. Analytical TLC was carried out on
commercially prepared plates coated with 0.25 mm of self-
indicating Merck Kieselgel 60 F254 and visualised by UV
light at 254 nm. Preparative scale silica gel flash chroma-
tography (for lab work) was carried out by standard
procedures using Merck Kieselgel 60 (230-400 mesh).
Where not stated otherwise, assume standard practices have
been applied. Note well: Yields and strengths given in the
text above are those which can be expected from the
processes operated under normal conditions; figures below
are quoted for individual experiments and may vary from
those quoted in the text.
of sodium bicarbonate (67.2 g, 0.78 mol) in water (800 mL)
added over 10 min with increased agitation. An effervescence
and mild exotherm of a few degrees, easily controlled by
water-cooling on this scale, resulted initially, which subsided
after the first third of this solution had been added. The
mixture was agitated for 1 h and allowed to stand; the
dichloromethane solution of crude bromophenol (3) was
separated and returned to a clean, dry vessel. DABCO (110
g, 0.98 mol, 1.26 equiv) was added as a solid in one portion,
again resulting in a modest exotherm (2-3 °C on this scale),
easily controlled by water cooling. A solution of DMTCC
(98.7 g, 0.80 mol, 1.03 equiv) in dichloromethane (600 mL)
was added evenly over 90 min. There was no detectable
exotherm. The resulting solution was agitated for 16 h at 20
°C, during which time some gelatinous solid may form
(thought to be DABCO‚2HCl), but which readily dissolved
during the aqueous workup. A solution of HCl (2.0 M, 480
mL) was added with rapid agitation, the resulting layers were
allowed to settle and were separated, with the upper aqueous
phase being discarded. The dichloromethane solution was
washed twice more with HCl (2 × 480 mL) and returned to
a dry vessel. The dichloromethane was removed by distil-
lation at atmospheric pressure until no more distillate was
observed (4.5 h on this scale; the temperature of the resulting
dark-orange oil rose to 58 °C). Methanol (480 mL) was added
evenly over 30 min to the crude concentrate with slow
agitation, maintaining the internal temperature. The resulting
solution was cooled at 10 °C/h and then held at 20 °C with
stirring for 3 h. A white solid usually crystallized during
the cooling phase, or occasionally during the addition of the
methanol. If after the hold time at 20 °C no solid had
appeared, addition of a pure seed of O-thiocarbamate or self-
seeding of the solution was always successful in crystallising
the product. The solid was isolated by vacuum filtration, and
the displacement was washed with ice-cold methanol (80
mL) and dried in a vacuum oven at 50 °C to yield the title
compound as a white crystalline solid (84.2 g, 37.4%). HPLC
purity 99.5%, tR 11.2 min (method A); mp 103-105 °C; 1H
NMR (400 MHz, CDC13) δ 7.45 (1H, dt, J ) 8.0, 1.1 Hz),
6.73 (1H, s), 6.72 (1H, dd, J ) 9.9, 2.9 Hz), 3.79 (3H, s),
3.47 (3H, s), 3.39 (3H, s); 13C NMR (100.6 MHz, CDC13)
δ 186.14, 159.55, 151.64, 132.98, 113.53, 111.12, 107.52,
55.68, 43.45, 38.93; MS (ES+) 290/292 (MH+, 1:1, 100%),
210 ((MH - Br)+, 42%).
Preparation of ZD2249 S-Thiocarbamate (5). A slurry
of O-thiocarbamate (4) (30.2 g, 104 mmols) in N,N-
diethylaniline (75.5 mL) was stirred in a vessel which was
evacuated by water-pump pressure for 20 min. The slurry
was then purged with either nitrogen or argon at atmospheric
pressure for 20 min. The evacuation was then repeated, but
the slurry was then purged overnight with stirring. The
reaction mixture was then heated to reflux (218 °C) for 7 h
to give a yellow solution which after this period was allowed
to cool freely to 20 °C overnight with stirring. In a separate
vessel, hydrochloric acid (6.0 M, 173 mL, 1.04 mol, 10.0
equiv) was cooled to 5 °C, and the reaction mixture was
added to it evenly over 30 min with rapid stirring. A brown
solid was immediately precipitated with a 7 °C exotherm
Preparation of ZD2249 O-Thiocarbamate (4) via
Bromophenol (3). A solution of 3-methoxyphenol (2) (96.3
g, 0.78 mol) in dichloromethane (600 mL) was cooled to 5
°C in a vessel connected to a sodium hydroxide scrubber
under a slow purge of nitrogen. A solution of bromine (107.6
g, 0.67 mol, 0.87 equiv) in dichloromethane (200 mL) was
added evenly over 90 min, and the solution allowed to warm
to 20 °C. The reaction mixture was quenched with a solution
Vol. 8, No. 1, 2004 / Organic Process Research & Development
•
41

on this scale, easily controlled by the rate of addition. The
resulting suspension was stirred for a further 30 min at 5 °C
before being isolated by vacuum filtration. The filter cake
was displacement-washed with water (90.6 mL), pulled dry
for 20 min, and then dried in a vacuum oven at 35 °C to
yield the title compound as an off-white or buff-coloured
crystalline solid (24.0 g, 65.7%). HPLC purity 96%, tR 9.2
kg, 35.75 mol, 1.0 equiv) in anhydrous THF (15 L) was
added evenly to the Grignard reagent over 2.5 h, keeping
the temperature below 30 °C, during which time an orange-
coloured solution formed, with some precipitation towards
the end of addition. After complete reaction, a solution of
ammonium chloride (16.8 kg) in water (42 L) was added
evenly over 2 h and the resulting suspension stirred at ∼20
°C for 15 h (there was a 10 °C exotherm initially on
addition). The layers were separated, and the lower aqueous
phase was extracted twice with ethyl acetate (15 L, then 10
L). All three organic portions were combined and dried over
magnesium sulfate (4 kg) in a dry vessel. The drying agent
was filtered off and washed with ethyl acetate (13 L), and
the combined organic portions were concentrated under
reduced pressure to yield the crude title compound as a red/
brown viscous oil (8.657 kg, 111%). HPLC purity 61.2%
giving a strength-corrected yield of 67.9% (5.88 kg).
Complete analytical data is reported in the chromatographic
purification section below.
Preparation of ZD2249 CBz Alcohol (8) by Lithiation
Reaction. Bromosulfide (6) (10.0 g, 42.9 mmol, 1.20 equiv)
and THF (77 mL) were cooled to -78 °C under an inert
atmosphere. N-Butyllithium (2.5 M in hexanes, 17.2 mL, 42.9
mmol, 1.20 equiv) was added dropwise over 30 min,
maintaining the temperature below -70 °C, followed by THF
(3 mL). A slurry of partially dissolved CBz piperidone (7)
(8.34 g, 35.75 mmol 1.0 equiv) in anhydrous THF (25.3 mL)
was added evenly to the lithiated reagent over 1.0 h, keeping
the temperature below -70 °C, followed by THF (3 mL).
During the addition the solution became darker. The reaction
mixture was stirred at -78 °C for ∼45 min. After complete
reaction, the reaction mixture was allowed to warm to 20
°C and quenched by the addition of a saturated solution of
ammonium chloride (65 mL) added evenly over 15 min. The
resulting layers were separated, and the aqueous phase was
extracted once with ethyl acetate (25 mL). The organic
portions were combined and concentrated to dryness under
reduced pressure to give the crude title compound (heavily
contaminated with product-related impurities) as a yellow,
viscous oil, 17.8 g (127%). HPLC purity 70.3% giving a
strength-corrected yield of 89% (12.5 g). Complete analytical
data is reported in the chromatographic purification section
below.
1
min (method A); mp 66-68 °C; H NMR (400 MHz,
CDC13) δ 7.54 (1H, d, J ) 8.8 Hz), 7.18 (1H, d, J ) 3.0
Hz), 6.82 (1H, dd, J ) 8.8, 3.0 Hz), 3.79 (3H, s), 3.08 (6H,
s); 13C NMR (100.6 MHz, CDC13) δ 165.16, 158.82, 133.65,
131.03, 123.01, 120.93, 117.44, 55.60, 37.03; MS (ES+) 290/
292 (MH+, 1:1, 100%).
Preparation of ZD2249 Bromosulfide (6). S-Thiocar-
bamate (5) (3.0 g, 10.3 mmol) was added in one portion to
a slurry of potassium hydroxide (1.5 g at 85% strength, 22.6
mmol, 2.2 equiv) in methanol (18 mL) and heated to reflux
(65 °C) for 2 h. The reaction mixture was then cooled to 5
°C, and methyl iodide (1.60 g, 11.3 mmol, 1.1 equiv) in
methanol (3.0 mL) was added evenly over 10 min. After
complete reaction, water (18 mL) was added to the reaction
mixture and stirred for 5 min to allow a cream precipitate to
redissolve. MTBE (18 mL) was added, and the mixture
stirred for 10 min; then the resulting layers were allowed to
settle and separate, and the lower aqueous layer was extracted
again with MTBE (18 mL). The combined MTBE layers
were washed with brine (9 mL) and then allowed to settle
and separate, and the MTBE layer was concentrated to
dryness by distillation at reduced pressure to yield the title
compound as a dark-coloured, crude oil (2.50 g, ∼100%).
An analytically pure sample was obtained by purification
with silica gel flash chromatography eluting in 4:1 hexane:
dichloromethane (Rf 0.34, SiO2) with 91% recovery. For plant
manufacture, azeotropic drying from a toluene solution was
required to remove residual methanol, bring the typical yield
down to ∼90%. HPLC purity (of crude oil) >98%, tR 9.4
min (method B); mp (light oil); 1H NMR (400 MHz, CDC13)
δ 7.39 (1H, d, J ) 8.6 Hz), 6.69 (1H, d, J ) 2.8 Hz), 6.56
(1H, dd, J ) 8.7, 2.8 Hz), 3.80 (3H, s), 2.46 (3H, s); 13C
NMR (100.6 MHz, CDC13) δ 159.42, 140.70, 133.12,
112.41, 112.27, 110.80, 55.54, 15.81; MS (EI+) 232/234
+
(M+, 1:1, 100%), 217/219 (M - CH3 , 1:1, 14%), 199/201
(M - SH+, 1:1, 23%), 138 (M - CH3Br+, 62%); and 310/
312/314 (dibromosulfide (17) M+, 1:2:1, 8%).
Purification of Crude ZD2249 CBz Alcohol (8) by
Large-Scale Chromatography. Chromatography was per-
formed on a 42-cm diameter polypropylene Nutsche, ex-
tended to 70-cm depth and specially manufactured for this
purpose. The base of the Nutsche had a paper filter covered
in a layer of sand onto which the silica “column” was loaded
as a slurry in 1:1 ethyl acetate:isohexane (eluent), with
another layer of sand on top. Standard flash chromatography
silica gel (230-400 mesh) was used at 14 times the mass of
the crude material to be purified. The crude CBz alcohol
was dissolved in an equal mass of eluent and loaded onto
the column. Aliquots of eluent were pulled through the
column by vacuum, using the dry flash technique, collecting
fractions containing pure CBz Alcohol; clean eluent fractions
were recycled on this scale. The product containing fractions
Preparation of ZD2249 CBz Alcohol (8) by Grignard
Reaction. Magnesium turnings (625 g, 25.68 mol, 1.28
equiv) were charged to a thoroughly dried vessel under an
inert atmosphere, followed by anhydrous THF (25 L) with
agitation. The agitation was stopped, and bromosulfide (6)
(702 g, 3.01 mol, 0.12 equiv) was added neat over several
minutes followed by iodine (0.5 g). Occasional stirring was
started to allow initiation of the reaction to occur, as detected
by an exotherm of up to 30 °C. Once initiation had occurred,
the remaining bromosulfide (5.146 kg, 22.07 mol, 0.88 equiv)
was added neat over 2.5 h, keeping the temperature below
30 °C. A final charge of THF (1 L) was added to wash in
residual bromosulfide, and the reaction mixture was stirred
for 16 h. A filtered solution of CBz piperidone (7) (4.681
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Vol. 8, No. 1, 2004 / Organic Process Research & Development

were concentrated on a 20-L rotary evaporator to give the
purified title compound as a viscous yellow oil initially,
which crystallized on standing and eventually seeded other
column fractions directly before concentration. Typical yields
and purity are given in the text. HPLC, tR 7.9 min (method
A); TLC (SiO2, 1:1 ethyl acetate:isohexane; methoxy sulfide
Rf 0.82; CBz alcohol Rf 0.33; CBz piperidone Rf 0.29); mp
90-91 °C; 1H NMR (400 MHz, CDC13) δ 7.28-7.38 (5H,
m), 7.24 (1H, d, J ) 8.8 Hz), 6.95 (1H, d, J ) 2.7 Hz), 6.70
(1H, dd, J ) 8.7, 2.7 Hz), 5.14 (2H, s), 4.10 (2H, bs), 4.05
(1H, s), 3.80 (3H, s), 3.38 (2H, bs), 2.51 (3H, s), 2.10 (2H,
bd, J ) 12.3 Hz), 1.99 (2H, bs); 13C NMR (100.6 MHz,
CDC13) δ 158.82, 155.35, 138.28, 137.00, 136.68, 128.48,
127.92, 127.88, 127.84, 126.49, 117.51, 110.88, 72.05, 67.01,
55.35, 39.96, 37.01, 36.91, 19.09; MS (ES+) 410 (M + Na+,
12%), 370 (MH+ - H2O, 65%), 326 (16%), 278 (21%), 201
(48%).
content of the resulting clear solution determined by Karl
Fischer titration. This solution was transferred to a thoroughly
dried reaction vessel containing CBz sulfide (10.85 g, 29.2
mmol, 1.00 equiv) under an inert atmosphere and stirred to
give a pale yellow solution. Titanium isopropoxide (8.96 mL,
29.2 mmol, 1.00 equiv) was added, followed by distilled
water (0.50 mL, 27.8 mmol, 0.95 equiv) sufficient to make
up the total water content of the reaction mixture to 1.00
equiv. The reaction mixture was cooled to -15 °C and
cumeme hydroperoxide (5.56 mL of an 80% w/w solution,
30.7 mmol, 1.05 equiv) added dropwise over 60 min,
maintaining the temperature at -15 °C. After 5-16 h the
reaction was complete, and a solution of 3 M HCl (60 mL,
200 mmol, 6.84 equiv) was added, allowing the mixture to
warm to 20 °C. (Note well. This addition is strongly
exothermic.) This was stirred at 20 °C for 1 h after which
the pale-yellow lower dichloromethane phase was separated
from the bright-orange upper aqueous phase and returned to
the reaction vessel. A solution of 4 M NaOH (66 mL, 264
mmol, 9.04 equiv) was added and the mixture heated to 40
°C for 1 h before cooling back to 20 °C. (Note well. This
addition can be exothermic at first if there is residual HCl
left in the organic phase.) The phases were separated, and
the lower dichloromethane phase was washed twice with
water (66 mL each, 6.1 volumes) before concentration under
reduced pressure to give the crude title compound as a pale-
yellow oil (15.55 g, 137.4%; 10.34 g, 91.4% corrected for
strength). HPLC purity, 96% by area, 66% against a standard;
tR 7.8 min. (method A); ee 93.6% (method C); mp (oil); 1H
NMR (400 MHz, CDC13) δ 7.52 (1H, d, J ) 2.8), 7.48 (1H,
m), 7.31-7.38 (4H, m), 7.17 (1H, d, J ) 8.6 Hz), 6.96 (1H,
dd, J ) 8.6, 2.8 Hz), 5.16 (2H, s), 4.33 (2H, vbs), 3.86 (3H,
s), 2.78-2.93 (3H, bm), 2.69 (3H, s), 1.60-1.94 (∼4H, bm);
13C NMR (100.6 MHz, CDC13) δ 159.54, 155.23, 144.17,
136.75, 133.87, 128.51, 128.19, 128.05, 127.94, 124.36,
118.56, 106.85, 67.22, 55.56, 44.51, 43.84, 36.86, 31.75; MS
(ES+) 387 (MH+, 100%), 344 ((MH - CO2)+, 21%).
Preparation of ZD2249 Methoxy Sulfoxide (1). CBz
sulfoxide (15.2 g @ 66.5%, 26.0 mmol, 1.0 equiv), IMS (76
mL, 5.0 volumes) and KOH (19.7 mL of 48/50% w/w
solution, 260 mmol, 10.0 equiv) were heated together at
reflux for 6 h, after which time the hydrolysis was complete.
The reaction mixture was concentrated to an oil, then toluene
was added (30.4 mL, 2.0 volumes) and re-concentrated to
ensure all the IMS had been removed. Fresh toluene (91 mL,
6.0 volumes) and water (38 mL, 2.5 volumes) were added,
and the mixture was cooled to 5 °C with stirring. Concen-
trated HCl (21.3 mL of 37% w/w solution, 260 mmol, 10.0
equiv) was added dropwise over 30 min, keeping the
temperature below 18 °C. (Note well. Some CO2 is liberated
during this addition, which is also exothermic; higher
temperatures may racemise the sulfoxide under these condi-
tions.) Water was added (30.4 mL, 2.5 volumes) and the pH
adjusted to 1 with additional HCl if necessary to reduce
losses of product to the toluene phase. After 15 min, the
phases were separated, and the lower product-containing
aqueous phase was washed with toluene (30.4 mL, 2.5
volumes) and separated again. A solution of NaOH (2.5 mL
Preparation of ZD2249 CBz Sulfide (9). Triethylsilane
(56.5 mL, 354 mol, 10.0 equiv) and trifluoroacetic acid (27.3
mL, 348 mol, 10.0 equiv) were mixed with stirring and
cooled to 10 °C. CBz alcohol (8) (13.7 g, 35.4 mmol, 1.0
equiv) was added as a solid in 10 equal portions at 10 min
intervals over a period of 1.5 h. After a further 30 min, the
reaction mixture was cooled to 0 °C and added to a cooled
saturated solution of sodium bicarbonate (440 mL) with
vigorous stirring. The addition rate was adjusted to control
some effervescence and a mild exotherm, but slow addition
was only necessary at the beginning. Dichloromethane (68
mL) was added with vigorous stirring for 10 min, the layers
were allowed to separate, and the pH was checked to be in
the range 7-8 (more sodium bicarbonate was added, if not).
The lower organic phase was separated and the solvent
removed under reduced pressure to give a crude oil which
was then dissolved in acetonitrile (82 mL). Isohexane (68
mL) was added with vigorous stirring, and after standing
the phases were separated. The lower acetonitrile phase was
washed twice more with isohexane (2 × 68 mL) and then
concentrated under reduced pressure to give a crude oil. This
was dissolved in ethyl acetate (14 mL) and heated to reflux,
and isohexane (56 mL) was added slowly. The solution was
cooled evenly to 20 °C over 3 h during which time a white
solid appeared and then was stood over ice for a further 2 h.
The solid was isolated by filtration, washed with isohexane
(15 mL), and dried in vacuo at 40 °C to yield the title
compound as a white solid (10.24 g, 78%). HPLC purity
99%, tR 37.0 min. (method A) or tR 21.7 min. (method B);
1
mp 84-85 °C; H NMR (400 MHz, CDC13) δ 7.30-7.39
(5H, m), 7.05 (1H, d, J ) 8.5 Hz), 6.76 (1H, d, J ) 2.7 Hz),
6.67 (1H, dd, J ) 8.5, 2.7 Hz), 5.16 (2H, s), 4.32 (2H, bs),
3.79 (3H, s), 3.07 (1H, tt, J ) 12.0, 3.3 Hz), 2.91 (2H, bt,
J ) 11.7), 2.45 (3H, s), 1.82 (2H, bd, J ) 12.7 Hz), 1.57
(2H, bm); 13C NMR (100.6 MHz, CDC13) δ 158.38, 155.34,
137.89, 136.98, 135.41, 128.49, 127.87, 126.45, 112.25,
109.95, 67.05, 55.31, 44.83, 38.03, 32.41, 16.00; MS (ES+)
372 (MH+, 100%), 328 ((MH-CO2)+, 41%).
Preparation of ZD2249 CBz Sulfoxide (10). (-)-Diethyl
D-tartrate (12.04 g, 58.4 mmol, 2.00 equiv) was dissolved
in dichloromethane (109 mL, 10.1 volumes) and the water
Vol. 8, No. 1, 2004 / Organic Process Research & Development
•
43

of 46/48% w/w solution, 44.0 mmol, 1.7 equiv) in water
(7.4 mL, 0.6 volumes) was added carefully to the aqueous
phase at 20 °C (a modest exotherm is observed on this scale).
After stirring for a few minutes, the pH was adjusted to >11
with additional NaOH if required to reduce product losses
to the aqueous phase in the following extractions. The
aqueous phase was extracted twice with dichloromethane (91
mL each, 6.0 volumes) and the combined dichloromethane
portions concentrated to dryness to give the crude title
compound as a pale-yellow viscous oil or white solid
(depending on quality and strength) (6.39 g, 96.9%). HPLC
purity 100%, tR 3.1 min (method A); ee 94.4% (method D);
heated back to reflux. A 10-mL portion was taken and
induced to crystallize in a clean beaker by scratching to
provide a seed which was added back to the main reaction
vessel. After a further 2 h at reflux, the solution was allowed
to cool to 20 °C overnight, during which time significant
crystallization occurred. The solution was cooled further to
0 °C for 2 h and then isolated by filtration on a Nutsche and
deliquored thoroughly. The product was washed with chilled
absolute ethanol (1374 mL, 1.0 volume) and then chilled
MTBE (2748 mL, 2.0 volumes) and dried in vacuo at 40 °C
to give the title compound as a white solid. HPLC and MS
1
data as for methoxy sulfoxide. Mp 181-182 °C; H NMR
1
mp 128-132 °C (sinters ∼120 °C); H NMR (400 MHz,
(400 MHz, d6-DMSO) δ 7.36 (1H, d, J ) 2.8 Hz), 7.32 (1H,
d, J ) 8.4 Hz), 7.10 (1H, dd, J ) 8.4, 2.8 Hz), 3.98 (2H, s),
3.81 (3H, s), 3.4-4.8 (vb), 3.33 (2H, bd, J ) 11.6 Hz), 2.89-
3.05 (3H, m), 2.69 (3H, s), 1.91-2.01 (1H, dq, J ) 13.2,
2.8 Hz), 1.80-1.88 (2H, m), 1.74 (1H, bd, J ) 13.2 Hz);
13C NMR (100.6 MHz, d6-DMSO) δ 174.56, 158.84, 145.02,
133.31, 127.81, 117.43, 107.17, 71.78, 55.37, 43.49, 43.30,
43.22, 33.58, 30.09, 28.66.
CDC13) δ 7.51 (1H, d, J ) 2.8 Hz), 7.27 (1H, d, J ) 8.5
Hz), 7.00 (1H, dd, J ) 8.6, 2.8 Hz), 3.87 (3H, s), 3.18 (2H,
bt, J ) 12.1 Hz), 2.70-2.79 (3H, m), 2.69 (3H, s), 1.57-
1.85 (∼5H, m); 13C NMR (100.6 MHz, CDC13) δ 159.30,
144.00, 135.08, 127.93, 118.46, 106.52, 55.69, 47.09, 43.85,
37.43, 35.03, 33.85; MS (ES+) 254 (MH+, 100%).
Preparation of ZD2249 Methoxy Sulfoxide Tartrate
Salt (11). Methoxy sulfoxide (1.616 kg @ 85%, 5.45 mol,
1.0 equiv) was heated to reflux in absolute ethanol (2.75 L,
2.0 volumes) to give a clear colourless solution. In a separate
vessel, L-(+)-tartaric acid (868 g, 5.723 mol, 1.05 equiv)
was heated to reflux in absolute ethanol (2.06 L, 1.5 volumes)
to give a clear colourless solution. Both solutions were
allowed to cool slightly, and the tartaric acid solution was
transferred by vacuum to the methoxy sulfoxide solution to
give a turbid solution which was heated back to reflux for 1
h. The clear solution was allowed to cool to 20 °C overnight,
but there was no crystallization. The solution was cooled to
3 °C over 3 h to give an oily emulsion. Further absolute
ethanol (2.75 L, 2.0 volumes) was added and the solution
Acknowledgment
We thank Steve Hallam and Paul Gillespie (Process
Hazards Section, Macclesfield) for the hazard studies; Steve
Baldwin, Nathalie Roberts, and Matt Young (Avlon) and later
Kate Arnot and Anne Williams (Macclesfield) for analytical
support; and Claire Ancell and Sophie Prottey for additional
experimental work. We also benefited from excellent coop-
eration on this project with our Research colleagues in
Wilmington, DE, and in particular from Daniel Hill.
Received for review September 1, 2003.
OP030039Z
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