Development of an enantioselective, kilogram-scale, rhodium-catalysed 1,4-addition

Article abstract of DOI:10.1021/op700246g

A rhodium-catalysed 1,4-addition of an arylboron species to an α,β-unsaturated ester was the key chirality-inducing step in the synthesis of an API. We describe herein the development of this chemistry, including optimization of reagent charges, reaction

Full text of DOI:10.1021/op700246g

Organic Process Research & Development 2008, 12, 496–502
Development of an Enantioselective, Kilogram-Scale, Rhodium-Catalysed
1,4-Addition
Sally Brock, David R. J. Hose, Jonathan D. Moseley, Alexandra J. Parker,* Ian Patel, and Andrew J. Williams
AstraZeneca, Global Process R&D, AVlon Works, SeVern Road, Hallen, Bristol BS10 7ZE, U.K.
Abstract:
mediated chemistry would also avoid both low temperatures
-70 °C) and the need to obtain ephedrine which is subject to
controlled-substances legislation in the U.K.
(
A rhodium-catalysed 1,4-addition of an arylboron species to an
r,ꢀ-unsaturated ester was the key chirality-inducing step in the
synthesis of an API. We describe herein the development of this
chemistry, including optimization of reagent charges, reaction
conditions, and metal recovery, in order to allow manufacture at
multikilogram scale. A key result was the unexpected discovery
that the use of a minimal quantity of an alcohol, rather than water,
reduces the extent of rhodium-mediated protodeboronation of the
boron species. This allowed the charge of this expensive reagent
to be significantly reduced. Furthermore, the use of an alcohol
instead of water avoided the agglomeration of the inorganic base
present in the reaction, making the process more robust and
operationally simpler. To our knowledge this is the first time that
this type of C-C bond-forming chemistry has been used in a
multikilo manufacture.
Results and Discussion
We first applied this chemistry to a series of compounds
1
where R in Scheme 2 was an aryl group. This work and the
identification of a previously unreported 1,3-addition product
3
2
(Scheme 3) will be reported elsewhere.
After working on this initial series our attention turned to a
second series of compounds where R ) 1-mesylpiperidin-4-
1
yl. In this case a different unsaturated ester 3 was required as
the substrate for the key 1,4-addition chemistry. This was
synthesized using the chemistry shown in Scheme 4. Thus, ethyl
isonipecotate was mesylated using standard conditions to give
ester 4. Ester 4 was reduced to the alcohol 5 using lithium
aluminium hydride, and then partially reoxidised to the aldehyde
6
via a Swern oxidation. A direct reduction of the ester 4 to
Introduction
the aldehyde 6 using DIBAL was investigated but was found
at this time to give unrealiable and unacceptable levels of over-
reduction to the alcohol 5: the best ratio achieved was 2:1 in
favour of the aldehyde 6. In fact, the aldehyde 6 was found to
be difficult to handle, forming what were presumed from mass
spectroscopy data to be dimers (7a or 7b) via aldol-type
chemistry, as well as a cyclic trimer 8 in protic solvents (Figure
Two related series of compounds with the general structure
(1) were required as part of a drug development program.
1). Consequently the aldehyde 6 was not isolated but was
reacted in situ with the mono-iso-propyl malonate 9, itself
prepared in solution by the reaction of iso-propanol with
Meldrum’s acid (10). After heating to effect decarboxylation,
this gave the unsaturated ester substrate 3 for our key chirality-
inducing, 1,4-addition step.
We also investigated the synthesis of 11 from the cheaper
ethyl isonicotinate (12) (Scheme 5). However, no desired
product 13 was detected from the key 1,4-addition reaction of
the arylboron with substrate 14. We believe this to be because
the substrate 14 coordinates to the rhodium atom via the pyridine
nitrogen atom, removing the metal from the catalytic cycle. In
support of this hypothesis we also found that we needed to
carefully control the level of piperidine present in 3 (Scheme
4) as high levels of this amine also resulted in catalyst poisoning
in the subsequent step.
Our colleagues in Medicinal Chemistry had successfully
made the first gram quantities of material 1 using the chemistry
shown in Scheme 1. The key step in this synthesis utilised an
ephedrine-based chiral auxiliary to control the facial selectivity
of a copper-mediated 1,4-addition of an aryl-Grignard.
However, we felt that the rhodium-catalysed 1,4-addition
of an arylboron species to an unsaturated ester offered a more
efficient way of introducing the required chirality, using a
disconnection which would readily accommodate potential
1,2
variation in the structural series (Scheme 2) In addition, this
approach would avoid the generation of copious quantities of
copper-contaminated waste, eliminate the need to use the
In contrast to our earlier work on cinnamate derivatives
3
2
expensive Bu BOTf reagent, and remove the need for a chiral
(Scheme 3), when the key 1,4-addition reaction was first tried
auxiliary that may not be recyclable. Furthermore, the rhodium-
on the new substrate 3 using the conditions shown in Scheme
3
there was no aryl insertion detected at the R-position, and
*
Author to whom correspondence may be sent. E-mail: alexandra.parker@
quantitative solution yield of the desired product in ∼90% ee
astrazeneca.com.
(
(
1) Hayashi, T. Synlett 2001, 879–887.
2) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829–2844.
(3) Williams, A. J.; Parker, A. J. Manuscript in preparation.
4
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10.1021/op700246g CCC: $40.75  2008 American Chemical Society
Published on Web 04/16/2008

Scheme 1. Medicinal Chemistry route
Scheme 2. Proposed alternative route
overall efficiency, as well as avoiding the need for the
technically difficult isolation of the product from neopentyl-
based byproduct of the process. The neopentyl boronate ester
had initially been used because it was commercially available,
and it had showed promise in an early screen of available 3,5-
difluorophenyl boronate species (boroxine, boronic acid, and
boronate esters) with the initial series of compounds where R
aryl (Scheme 3). However, it was demonstrated that the
1
)
reaction also proceeded well with 3,5-difluorophenyl boronic
acid (15) or with the corresponding boroxine (16) (Scheme 6).
In fact, it was later found that some commercial supplies of
was achieved. However, as well as further improving the ee,
there were several issues that required resolution in order to
provide larger quantities of material:
“
boronic acid” actually contained a significant proportion of
boroxine, and further work on the impact of this is ongoing.
A catalytic quantity of K PO was sufficient for the boronate
ester-based reaction, but a stoichiometric charge of K PO was
•
The initial conditions required the use of 3.5 mol equiv
of neopentyl 3,5-difluorophenylboronate ester, which
was found to be a very expensive starting material
3
4
3
4
(
£5600/kg for 1 kg). Most of this boronate ester was
required, as might be predicted from the proposed mechanism
(Scheme 7), when using the boronic acid (15). However, this
wasted via rhodium-mediated hydrolysis to difluo-
robenzene (vide infra).
4
,5
increased amount of K
the nonhomogeneity of the reaction even more marked. A
switch from K PO to K CO was made, because the latter is
3 4
PO made the issues associated with
•
The mixture of inorganic base and water used in the
initial conditions resulted in a coating of solid on the
vessel walls and agglomeration of solid into large lumps
within the reaction mixturesclearly undesirable for
scale-up.
3
4
2
3
more readily available in a finely ground form (“325 mesh”)
which was found to be beneficial on scale-up. A further key
result was the discovery that the use of a small amount of an
•
•
The removal of neopentyl glycol-related species from
the product.
The presence of rhodium in the product at an unac-
ceptably high level (typically ∼200 ppm).
2 3
alcohol in place of water allowed the finely divided K CO to
remain uniformly suspended throughout the reaction, rather than
settling in lumps at the bottom of the reactor and coating the
reactor walls. Although not an issue on a small scale, the
physical behaviour of the base became very important on scale
up, when the rate of reaction was found to be unacceptably
slow using a water-based system.
The first three issues were solved by a combination of several
changes: the use of iPrOH in place of water, the use of K
in place of K PO , and the use of 3,5-difluorophenyl boronic
acid (15) in place of the corresponding neopentyl glycol ester
Scheme 3).
,5-Difluorophenyl boronic acid (15) was approximately one-
2 3
CO
3
4
(
3
(
6) (a) See for example: Amengual, R.; Michelet, V.; Genêt, J.-P. Synlett
002, 1791–1794. (b) Hayashi, T.; Takahashi, M.; Takaya, Y.;
seventh the price of its neopentyl glycol ester (£750/kg
compared to £5600/kg at the time of this work). In addition,
use of the boronic acid eliminated the need to prepare the
boronate ester as part of the manufacture, thus increasing the
2
Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052–5058. (c) Sakuma,
S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944–8946. (d) Sakuma, S.;
Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951–
5955. (e) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J. Am. Chem. Soc. 1998, 120, 5579–5580. (f) Takaya, Y.; Senda,
T.; Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asym-
metry 1999, 10, 4047–4056. (g) Navarre, L.; Pucheault, M.; Darses,
S.; Genet, J-P. Tetrahedron Lett. 2005, 46, 4247–4250. (h) Chen, G.;
Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285–2288.
(
4) Senda, T.; Ogassawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852–
856.
5) Boiteau, J-G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett.
003, 5, 681–684.
6
(
2
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Scheme 3. Identification of 1,3-addition product 2
Scheme 4. Synthesis of substrate 3 for rhodium-catalysed 1,4-addition
To date there are many examples of rhodium-catalysed 1,4-
additions to unsaturated esters, ketones, amides, and analogues
thereof in the literature. In these publications an excess of boron
of the ester group during the reaction. This key discovery8
should be applicable to other rhodium-catalysed 1,4-additions
to different substrates.
6
species is used (2 equivalents or moressometimes as much as
It was thought that the steric bulkiness of the ester group
might affect the ee. Thus, the ethyl and tert-butyl ester analogues
of 3 were synthesized and subjected to the standard reaction
conditions (Scheme 8).
1
0 equivalents) due to the competing rhodium-mediated pro-
todeboronation of the boron species under the process conditions
Scheme 7). It is postulated that the mechanism of protodebo-
(
ronation involves an aryl-rhodium species being intercepted by
a molecule of water or alcohol to form the corresponding arene.
These reactions all proceeded to completion, and the ee’s
were 37, 90, and 92% for the ethyl, iso-propyl, and tert-butyl
ester substrates, respectively. However, the tert-butyl substrate
reacted much more slowly than the iso-propyl variant (>24 h
vs 2–4 h for the iso-propyl substrate) which could mean that a
greater proportion of the boronic acid reagent would degrade
via protodeboronation during the reaction. Thus, the optimal
balance between ee and reaction rate could be achieved by using
the iso-propyl ester. The ee was further optimised to >99.5%
19
7
Following the reactions by F NMR enabled us to show that
the extent of rhodium-mediated protodeboronation of 3,5-
difluorophenyl boronic acid is less in the presence of an alcohol
than in the presence of water (Figure 2). Thus, the use of a
minimum amount (<2 equiv) of iso-propanol instead of water
allowed the charge of 3,5-difluorophenyl boronic acid, still
representing the highest proportion of the cost of raw materials
in this manufacture, to be reduced from 3.5 equiv to 1.35 equiv.
iso-Propanol was chosen to avoid any possible transesterification
(
7) 3,5-Difluorophenyl boronic acid was charged to a small volume reactor
(4 mL capacity). Finely ground potassium carbonate (7.5 mol%) and
trifluoromethylbenzene (∼0.3 mol equiv, used as an internal standard)
were charged before dissolving the mixture in anhydrous THF and
adding either water or iso-propanol (1.5 mol equiv). A catalyst solution
of [Rh(COD)Cl]2 (0.015 mol equiv) and (R)-BINAP (0.037 mol equiv)
was prepared and allowed to completely dissolve and then stand under
a nitrogen atmosphere for 10 min before use. A diluent stock solution
comprising of DMSO-d6 (10 mL), acetic acid (500 µL [to quench the
1
9
reaction]) and trifluoroacetic acid (5 µL [internal reference for the
F
NMR]) was prepared in a 100 mL volumetric flask and made up to
the mark with DMSO (nondeutrated). This stock solution was used
to dilute the reaction samples (see below). The reaction was heated to
6
0 °C and maintained at that temperature throughout the course of
the reaction. At set intervals, samples were removed (20 µL) and
diluted with the DMSO stock solution (980 µL). The sampling times
were 0, 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 600, 720, 840,
9
60, 1200, and 1440 min.
8) Williams, A. J.; Patel, I.; Oldfield, J. Int. Pat. Appl. WO2007/057643,
007.
(
(
2
9) Smopex-234 is commercially available for GMP manufacture from
Johnson-Matthey (http://www.smopex.com) who can also arrange for
metal recovery from reaction residues.
Figure 1. Proposed structures of impurities. Protodeboronation
of 3,5-difluorophenyl boronic acid.
(
10) Bunten, K. A.; Farrar, D. H.; Poë, A. J.; Lough, A. Organometallics
2002, 21, 3344–3350.
4
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Scheme 5. Attempted alternative synthesis
Scheme 6. Interconversion of boronic acid and boroxine
times. All the scavengers demonstrated at least some capacity
to adsorb rhodium, but Smopex-234 was chosen for further
development because of its low cost relative to the others and
because it is approved for use in GMP manufacture.9
A laboratory reaction to test Smopex-234 on a slightly larger
scale was carried out. Unexpectedly the rhodium content of this
reaction mixture after treatment with Smopex-234 was signifi-
cantly higher than in the corresponding robot reaction. Similarly,
in the earlier reactions when cysteine had been used for rhodium
removal, it had also been found that the rhodium content was
higher when the reaction was done on 3 kg scale than it had
been on a smaller scale in normal laboratory glassware. So it
seemed that rhodium removal was generally less efficient on a
larger than on a smaller scale.
A possible reason for this was that the smaller-scale reactions
were less well inerted in both cases. On the robot the reaction
itself had been carried out under inert conditions, but the
Smopex-234 treatment had not, whereas both stages of the
comparable laboratory experiment had been rigorously inerted.
Similarly, it is often found that inertion improves on scale-up,
and this could explain why rhodium removal was less efficient
using cysteine on the 3-kg scale than in the laboratory. It is
postulated that exposure to oxygen may cause oxidation of the
BINAP ligand,10 which could release the metal into solution
and facilitate its removal by either cysteine or Smopex-234.
Alternatively, the physical removal of the insoluble oxidised
BINAP-rhodium complex by filtration may contribute to lower
2
by ensuring that the catalyst precursor, [Rh(cod)Cl] , and the
phosphine ligand were premixed for a sufficient time before
addition of the other components of the reaction.
The final issue that required resolution before scale-up was
the removal of rhodium to an acceptable level in the product.
In earlier manufactures, rhodium levels in the ester (17) were
typically >200 ppm and were not significantly reduced during
downstream processing to the final API. For the initial
manufacture of three batches, each giving around 3 kg of ester
product (17), a wash of an organic solution of the product with
aqueous cysteine was chosen as a cheap and readily available
method of rhodium removal. However, this still gave product
containing 60–90 ppm rhodium, which was only acceptable for
very early toxicology studies.
Subsequent to this first manufacture, further rhodium re-
moval methodologies were investigated. Using our Zymark
robotic system, twenty-two commercially available rhodium
scavengers were added to a reaction solution that had achieved
the required 1,4-addition. These samples were heated to 60 °C
for 20–24 h and sampled for rhodium-content by XRF at various
Scheme 7. Proposed mechanism
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499

scaled up to two batches each starting with 27 kg of substrate
3), the rhodium level in the product (17) was consistently <30
(
ppm, which translated to well below our 10 ppm target for the
final API. Careful rhodium tracking during the manufacture
showed that 99.6% of the input rhodium can be accounted for,
with 97% being removed by the combination of Oxone and
Smopex-234. In addition the Smopex-234 can be returned to
the supplier for rhodium recovery.
Conclusion
A rhodium-catalysed enantioselective 1,4-addition has been
scaled up to provide more than 50 kg of product (17) in two
batches, in an average yield of 74%, not including the material
lost to the filtration “heel”. The product had an assay of 99%
and contained less than 0.5% w/w of the undesired enantiomer
and the rhodium content was <30 ppm. Thus, the applicability
of this powerful C-C bond-forming methodology has been
demonstrated on a kilogram scale for the first time within
AstraZeneca. Several changes to previously published proce-
dures have been incorporated in order to make this reaction
more amenable to scale-up. Most significantly, these changes
involved: the use of an alcohol instead of water to enable
minimization of the charge of expensive boron species and to
improve the “form” of the reaction suspension; and the use of
an oxidant to facilitate removal of rhodium from the product.
These changes should be generally applicable to this reaction
with other substrates.
Figure 2. Protodeboronation of 3,5-difluorophenyl boronic
acid.
Scheme 8. Standard reaction conditions
Experimental Section
General. Starting materials, reagents, and solvents were
obtained from standard commercial suppliers and were used
1
without further purification. H NMR spectra were recorded at
400 MHz on a Bruker-400 instrument. Reaction progress was
followed either by GC (using an Agilent 6890N GC, fitted with
a DB-5 column with dimensions of 30 m × 0.32 mm and 1
µm particle size, and using a temperature profile from 150 to
325 °C at 25 °C/min) or by LC (using an Agilent 1100 LC,
levels of rhodium in the product, or the oxidant may change
the oxidation state of the metal and facilitate its removal from
solution.
At AstraZeneca the Basis of Safety for plant operation
typically relies on the exclusion of oxygen from the presence
of flammable materials. Hence an alternative oxidant to
atmospheric oxygen was required to aid rhodium removal. The
effect of a variety of oxidants on the removal of rhodium from
the THF reaction solution was examined. After completing the
fitted with a ThermoElectron Betabasic 18 column with
dimensions of 15 cm × 4.6 mm and 3.5 µm particle size, and
eluting with a solvent gradient from 35% to 95% of MeCN/
water containing 0.1% formic acid over 10 min).
Preparation of 1-Methanesulfonyl-4-(ethoxycarbony1)-
piperidine (4). Ethyl isonipecotate (1 mol equiv) was charged
to a reaction vessel followed by a line wash of DCM (1 rel
vol). Triethylamine (1 mol equiv) was charged to the vessel
followed by a line wash of DCM (1 rel vol). DCM (5 rel vol)
was charged to the vessel and the reaction mixture cooled to
between 0 and 5 °C. A solution of methane sulfonyl chloride
(1 mol equiv) in DCM (2 rel vol) followed by a line wash of
DCM (1 rel vol) was added to the vessel while maintaining
the temperature between 1 and 10 °C. The reaction mixture
was stirred at between 0 and 10 °C until the reaction was
complete. Purified water (5 rel vol) was charged and the reaction
mixture was stirred for 15 min at between 5 and 10 °C. The
resulting phases were separated and the organic phase was
concentrated to approximately 4.5 rel vol by atmospheric
distillation. The concentrate was clarified, and then di-iso-
propylether (10 rel vol) was added and the reaction concentrated
1
,4-addition, reactions containing mCPBA, MnO
Oxone, H , and NaOCl were stirred for 1 h before Smopex-
34 was added. These reactions were compared to two control
2
, NBS, NCS,
2 2
O
2
reactions: one with no oxidant, and the other with no oxidant
and no Smopex-234. In many cases the addition of oxidant
caused an immediate change from deep red to pale yellow/
orange, a colour change that is associated with catalyst
deactivation. The lowest level of rhodium was achieved using
Oxone, and so the combination of this with Smopex-234 was
further investigated, varying the temperature and loading of the
Smopex-234 resin to finally optimise rhodium removal. When
these reaction and workup conditions were applied together and
5
00
•
Vol. 12, No. 3, 2008 / Organic Process Research & Development

again to approximately 4.5 rel vols by reduced pressure
distillation. Another portion of di-iso-propylether (10 rel vol)
was added and the resulting suspension was stirred at ambient
temperature for at least 60 min. The solid was isolated by
filtration, washed with di-iso-propylether (2 rel vols) and then
while cooling the reaction in an ice–water bath. DCM (5 rel
vol) was added before separating the layers and washing the
DCM layer with HCl (2 M, 5 rel vol), then sodium bicarbonate
solution (saturated, 5 rel vol), and finally brine (5 rel vol). The
organic solvent was removed from the organic phase in vacuo
dried at ambient temperature to give the title compound in
to leave a concentrated solution of the title compound in
1
1
approximately 93% yield. H NMR (400 MHz, DMSO-d
6
) δ
approximately 75% yield. H NMR (400 MHz, CDC1
3
) δ 9.69
4
3
)
.05 (q, J ) 7.1 Hz, 2H), 3.46 (d, J ) 12.0 Hz, 2H), 2.81 (s,
H), 2.76 (t, J ) 11.5 Hz, 2H), 2.48 – 2.38 (m, lH), 1.90 (d, J
13.3 Hz, 2H), 1.56 (dd, J ) 35.4, 3.5 Hz, 2H), 1.16 (t, J )
(s, lH), 3.68-3.54 (m, 2H), 2.96 (ddd, J ) 12.3, 9.7, 2.8 Hz,
2H), 2.78 (s, 3H), 2.43 (dquintet, J ) 9.5, 4.7 Hz, lH),
2.10-2.00 (m, 2H), 1.81 (dtd, J ) 13.8, 9.8, 3.9 Hz, 2H).
Preparation of iso-Propyl Malonic Acid (9). Meldrum’s
acid (10, 1 mol equiv) was charged to a reaction vessel followed
by toluene (5 rel vol) and iso-propanol (0.59 rel vol). The
reaction mixture was heated to between 85 and 90 °C until the
reaction was complete. The reaction mixture was then cooled
to ambient temperature and transferred to a suitable storage
container, washing the vessel with toluene (1 rel vol) and adding
this wash to the solution of the title compound.
7.2 Hz, 3H).
Preparation of (1-Methanesulfonylpiperidin-4-y1)methanol
(5). 1-Methanesulfonyl-4-(ethoxycarbony1)-piperidine (4) (1
mol equiv) was charged to a reaction vessel followed by a line
wash of THF (6 rel vols). The reaction mixture was cooled to
between 0 and 10 °C. A solution of lithium aluminium hydride
(1 M in THF, 0.75 mol equiv) followed by a line wash of THF
(1 rel vol) was added to the vessel, keeping the temperature
between 0 and 20 °C, and then the reaction mixture was warmed
to ambient temperature and stirred until the reaction was
complete. The reaction mixture was cooled to between 0 and
Preparation of iso-Propyl 3-(1-methanesulfonylpiperidin-
4-yl)propenoate (3). (1-Methanesulfonylpiperidin-4-yl)metha-
nal (6, l mol equiv) was charged to a reaction vessel followed
by a line wash of toluene (11 rel vol). Piperidine (0.1 mol equiv)
was charged to the vessel followed by a line wash of toluene
(0.5 rel vol) and the reaction mixture heated to between 85 and
95 °C. A solution of the iso-propyl malonic acid (9, 1.25 mol
equiv) in toluene (prepared as described above) was added in
10 approximately equal portions over 6-8 h, and the reaction
mixture was stirred at between 85 and 95 °C until it reached
completion. The reaction mixture was then cooled to between
40 and 50 °C, and HCl (0.5 M, 3 rel vol) was added to the
reaction, maintaining the temperature between 40 and 50 °C.
After stirring for at least 15 min the phases were separated.
Sodium bicarbonate (0.5 M, 3 rel vol) was added to the organic
phase, still maintaining the temperature between 40 and 50 °C.
The two-phase mixture was stirred for at least 15 min before
separating the phases and washing the organic phase with water
(3 rel vol). The organic phase was then concentrated to
approximately 16 rel vols by vacuum distillation at between
40 and 50 °C. Toluene (3.5 rel vol) was charged, and the
solution was clarified at between 40 and 50 °C and then
concentrated to approximately 7 rel vol by vacuum distillation.
The mixture was then cooled to between 0 and 10 °C and stirred
for at least 60 min at this temperature before isolating the title
compound by filtration and washing the solid product with
toluene (2 rel vol) at between 0 and 10 °C. The solid was dried
2
°C. Purified water (1 rel vol) was then charged to the vessel
maintaining the temperature between 0 and 10 °C. The pH of
the reaction was adjusted to <2 by charging 5 M HC1,
maintaining the temperature between 0 and 10 °C. The reaction
mixture was warmed to room temperature and stirred for at
least 15 min; the phases were then separated. DCM (5 rel vol)
was charged to the aqueous phase and stirred for at least 15
min after which the phases separated. The first organic (THF)
phase was concentrated to approximately 3.5 rel vols by vacuum
distillation at 40 °C. The second organic (DCM) phase was
added to the concentrate, the phases were separated, and the
organic phase was concentrated to approximately 3.5 rel vol
by atmospheric distillation. Di-iso-propylether (10 rel vol) was
added to the residue from the distillation at 40-45 °C. After
concentration to approximately 5 rel vol by vacuum distillation
more di-iso-propylether (5 rel vol) was added, and the resulting
slurry was cooled to ambient temperature and stirred for
approximately 60 min. The product was isolated by filtration,
washed with di-iso-propylether (2 × 1 rel vol), and dried at
ambient temperature to give the title compound in approxi-
1
mately 87% yield. H NMR (400 MHz, CDCl
3
) δ 3.84 (dd, J
)
9.6, 2.2 Hz, 2H), 3.54 (d, J ) 4.9 Hz, 2H), 2.78 (s, 3H),
2.67 (t, J ) 12.0 Hz, 2H), 1.70-1.56 (m, 2H), 1.54 (s, lH),
.36 (qd, J ) 12.5, 4.2 Hz, 2H).
1
1
Preparation of (1-Methanesulfonylpiperidin-4-y1)methanal
to give the title compound in approximately 59% yield. H
(
6). A solution of DCM (5 rel vol) and oxalyl chloride (3 mol
equiv) was cooled to below- 70 °C. In a separate vessel, DCM
2 rel vol) and DMSO (6 mol equiv) were mixed before addition
3
NMR (400 MHz, CDCl ) δ 6.87 (dd, J ) 15.8, 6.5 Hz, lH),
5.81 (dd, J ) 15.8, 0.9 Hz, lH), 5.07 (quintet, J ) 6.2 Hz, lH),
3.82 (d, J ) 12.0 Hz, 2H), 2.79 (s, 3H), 2.74 (td, J ) 12.0, 2.4
Hz, 2H), 2.36-2.17 (m, lH), 1.95-1.80 (m, 2H), 1.57 (ddd, J
) 24.9, 11.7, 4.0 Hz, 2H), 1.27 (d, J ) 6.4 Hz, 6H).
Preparation of (R)-iso-Propyl 3-(3,5-difluorophenyl)-3-
(1-(methylsulfonyl)piperidine-4-ylpropanoate (17). (R)-BI-
(
to the oxalyl chloride solution via a syringe, keeping the
temperature below -64 °C during the addition. After stirring
for 10 min a solution of (1-methanesulfonylpiperidin 4-yl)
methanol (5) (l mol equiv) in DCM (5 rel vol) and DMSO (0.5
rel vol) was added, keeping the temperature below -60 °C
during the addition. The reaction mixture was held at -70 °C
for 40 min before adding triethylamine (7.5 mol equiv) slowly
via a syringe. The reaction mixture was allowed to warm to
room temperature overnight. HCl (2 M, 5 rel vol) was added
2
NAP (0.0225 mol equiv) and [Rh(COD)Cl] (0.01 mol equiv)
were charged to a well-inerted reaction vessel. THF (2.8 rel
vol) was added, and the mixture was stirred to achieve
dissolution (at least 15 min). Meanwhile, iso-propyl 3-(1-
methanesulfonylpiperidin-4-yl)propenoate (3, 1.0 mol equiv),
Vol. 12, No. 3, 2008 / Organic Process Research & Development
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501

3
,5-difluorophenylboronic acid (1.35 mol equiv), and potassium
before cooling the reaction to 50 °C. MTBE (1.5 rel vols) was
used to wash the solid on the filter before being added to the
iso-propanol solution of the product. A small sample was
removed to provide seed crystals. The solution was then cooled
at 12 °C per minute to 20 °C (seed crystals were added at around
40 °C if required). After holding at 20 °C overnight, the title
compound was isolated by filtration under suction and washed
on the filter with iso-propanol (3.5 rel vol). After drying at
carbonate (1.35 mol equiv) were charged into a second well-
inerted reaction vessel. THF (7.8 rel vol) and iso-propanol (1.0
mol equiv) were then added, and the mixture was stirred and
heated to 60 °C. The catalyst solution in the first vessel was
charged to the second vessel. THF (1.4 rel vol) was charged to
the first vessel and then transferred to the main vessel as a line
wash. The batch was held at 60 °C until the reaction was
complete. Water (2 rel vol) was charged to the reaction at
5
0 °C under reduced pressure the product was obtained in 75%
60 °C. After stirring for at least 15 min, the phases were
1
yield. H NMR (400 MHz, DMSO-d
.02 (3H, d, J ) 6), 1.10 (lH, qd, J ) 12.5 and 4), 1.18 (lH,
qd, J ) 12.5 and 4), 1.33 (lH, d, J ) 12.5), 1.60 (lH, m), 1.88
lH, d, J ) 12.5), 2.49–2.66 (3H, m), 2.80 (lH, dd, J ) 15 and
), 2.81 (3H, s), 2.91 (lH, m), 3.46 (lH, d, J ) 12), 3.57 (lH, d,
J ) 12), 4.71 (lH, septet, J ) 6), 6.98 (2H, dd, J ) 8 and 1.5),
.05 (lH, tt, J ) 9.5 and 1.5).
6
) δ 0.96 (3H, d, J ) 6),
separated, and the remaining organic phase was washed with
brine (2 rel vols) at 60 °C. Oxone (0.09 mol equiv) was charged
to the organic layer, and the mixture stirred for 1 h at 60 °C.
Water (2 rel vol) was charged, the mixture was stirred, and the
phases were then separated to remove the Oxone. Smopex-
1
(
5
234 was charged to the reaction vessel, and the contents were
7
stirred for 24 h at 60 °C or until an appropriate reduction in
level of rhodium was achieved. The solution was then filtered
to remove the Smopex-234, and THF (2 rel vol) was charged
to the vessel as a line wash and combined with the product
solution. The combined THF phase was then concentrated to
Acknowledgment
We thank Bob Osborne, John Latimer, and Paul Murray for
help with the robotic reaction screening work, Gordon Plummer
for XRF analysis, and Rhian Thomas for the synthesis of key
intermediates.
3.5 rel vol. iso-Propanol (12 rel vol) was added and further
concentration to 3.5 rel vol performed, followed by a final refill
of iso-propanol (10.5 rel vol). The reaction was then cooled to
3
0 °C for 30 min in order to precipitate out any remaining low-
solubility impurities. After reheating the reaction to between
0 and 75 °C, the impurities were removed by a hot filtration
Received for review October 30, 2007.
OP700246G
7
5
02
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Vol. 12, No. 3, 2008 / Organic Process Research & Development