The synthesis of OSU 6162: Efficient, large-scale implementation of a Suzuki coupling

Article abstract of DOI:10.1021/op025620u

The synthesis of the chiral, nonracemic 3-aryl piperidine, OSU 6162 (1), a potential CNS agent from Pharmacia Corporation, is presented. The key construction in the described synthesis is a palladium-catalyzed aryl cross-coupling reaction between bromosulfone (4) and pyridyl borane (14). Initially developed conditions for this Suzuki reaction, conducted in tetrahydrofuran/aqneous hydroxide, delivered free base (6) or hydrochloride salt (15a) in reproducible 80% yield. However, by changing the solvent to toluene and the base to carbonate, significant decreases in catalyst requirement were realized, and the methane sulfonate salt (15b) of the coupled product could be obtained in reproducible 92-94% yield on 200-kg input. The success of the Suzuki reaction was critically dependent on a bulk source of the pyridyl borane coupling partner. Cryogenic conditions were developed for its generation via lithium-halogen exchange to generate thermally labile 3-lithiopyridine followed by transmetalation with diethylmethoxy borane. This highly exothermic series of transformations yielded crystalline diethyl-3-pyridyl borane in reproducible 75-80% yield on scales ranging up to 200-kg input. Selective reduction of the biaryl, classical resolution and introduction of the propyl group via the Gribble reductive amination procedure completed the synthesis of OSU 6162 free base. This route was employed to deliver over 35 kg of clinical-quality bulk drug in short order.

Full text of DOI:10.1021/op025620u

Organic Process Research & Development 2003, 7, 385−392
The Synthesis of OSU 6162: Efficient, Large-Scale Implementation of a Suzuki
Coupling
Michael F. Lipton,*,† Michael A. Mauragis,† Mark T. Maloney,† Michael F. Veley,† Dale W. VanderBor,†
John J. Newby,† Robert B. Appell,‡ and Edward D. Daugs‡
Early Process Research and DeVelopment, Pharmacia Corporation, 7000 Portage Road,
Kalamazoo, Michigan 49001, U.S.A., and Dow Pharmaceutical SerVices, The Dow Chemical Co.,
Midland, Michigan 48674, U.S.A.
Abstract:
requisite methyl sulfone moiety. Despite the known3 insta-
bility of 3-metallopyridines and their general lack of avail-
ability, the latter route, depicted in Scheme 1, appeared more
promising on paper. This aryl cross-coupling route was
therefore explored for viability, and its development is the
subject of this report.
The synthesis of the chiral, nonracemic 3-aryl piperidine, OSU
6162 (1), a potential CNS agent from Pharmacia Corporation,
is presented. The key construction in the described synthesis is
a palladium-catalyzed aryl cross-coupling reaction between
bromosulfone (4) and pyridyl borane (14). Initially developed
conditions for this Suzuki reaction, conducted in tetrahydro-
furan/aqueous hydroxide, delivered free base (6) or hydrochlo-
ride salt (15a) in reproducible 80% yield. However, by changing
the solvent to toluene and the base to carbonate, significant
decreases in catalyst requirement were realized, and the
methane sulfonate salt (15b) of the coupled product could be
obtained in reproducible 92-94% yield on 200-kg input. The
success of the Suzuki reaction was critically dependent on a
bulk source of the pyridyl borane coupling partner. Cryogenic
conditions were developed for its generation via lithium-
halogen exchange to generate thermally labile 3-lithiopyridine
followed by transmetalation with diethylmethoxy borane. This
highly exothermic series of transformations yielded crystalline
diethyl-3-pyridyl borane in reproducible 75-80% yield on
scales ranging up to 200-kg input. Selective reduction of the
biaryl, classical resolution and introduction of the propyl group
via the Gribble reductive amination procedure completed the
synthesis of OSU 6162 free base. This route was employed to
deliver over 35 kg of clinical-quality bulk drug in short order.
Results and Discussion
Reaction of dibromide 2, in what we believe is simply a
nucleophilic displacement, is straightforward. Thus, portion-
wise addition of an equimolar amount of solid sodium
thiomethylate to 1,3-dibromobenzene in warm N-methylpyr-
rolidinone or dimethyl formamide affords the desired thio-
ether in about 86% isolated yield. We found that better results
were obtained downstream in the synthesis if the displace-
ment was stopped after about 90% consumption of the
starting material. With ca. 10% dibromide remaining, the
reaction product competes effectively with the substrate for
thiomethoxide, thus generating the bis-thioether. This bis-
thioether, after oxidation to the bis-sulfone at the next step,
is not efficiently rejected later in the sequence.
Thioether 3, after an extractive workup, is taken up in
acetic acid and oxidized via the careful, controlled addition
of hydrogen peroxide. Oxidation of the thioether to sulfoxide
9 is extremely exothermic, fairly typical for such chemistry,
and to control the exotherm, we elected to slowly dose in
1.0 equivalents of hydrogen peroxide. Only after the exo-
therm from this oxidation had subsided did we add the
second equivalent of peroxide.
Introduction
OSU 6162 has been known in the literature since 1994,
and two syntheses of this chiral nonracemic 3-aryl piperidine
have been reported.1,2 The chemical structure is depicted
below.
Stirring overnight at elevated temperature consumed all
of the sulfoxide, as determined by TLC, since HPLC assay
methods proved unreliable in this instance. After a starch
iodide paper test to ensure that all of the peroxide had been
consumed as well, the acetic acid was removed under vac-
uum and replaced with 2-propanol to crystallize the product.
The initially reported synthesis1 suffered from unserviceable
yields for the multistep conversion of a phenol into the
(1) Sonesson, C.; Lin, C.-H.; Hansson, L.; Svensson, K.; Carlsson, A..; Smith,
M. W.; Wikstrom, H. J. Med. Chem. 1994, 37, 2735.
(2) Sonesson, C.; Lindborg, J. Tetrahedron Lett. 1994, 9063.
(3) Gilman, H.; Spatz, S. M. J. Org. Chem. 1951, 16, 1485.
* Corresponding author. E-mail: michael.f.lipton@pharmacia.com.
† Pharmacia Corporation.
‡ The Dow Chemical Co.
10.1021/op025620u CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/08/2003
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
385

Scheme 1
The isolated yield of crystalline 3-bromomethylphenyl sul-
fone was 79.8%, corrected, on scale. Although this chem-
istry was certainly adequate for the preparation of the sul-
fone in quantity and was in fact used to prepare some 29
kg, it suffered from the extremely high cost of sodium
thiomethylate, and this methyl sulfone preparation was
supplanted during our second, larger pilot-plant campaign
with material made by a commercial supplier using alterna-
tive technology.
Scheme 2
transmetalation reaction are very energetic. With the gener-
ally inefficient cooling that one sees on scale, and our
confirmation of Gilman’s observation of the thermal lability
of 3-pyridyllithium, it was clear that we would require
extended reaction times to run the process within these strict
temperature requirements. We charged n-butyllithium to the
hexane/MTBE mixture at -20 °C, cooled the mixture, and
slowly added the 3-bromopyridine, maintaining the temper-
ature below -40 °C. Under these conditions, the metalated
species is completely insoluble and precipitated as it was
formed, thus protecting it from further reaction. The DEMB
was then added, keeping the temperature below -30 °C. The
still heterogeneous reaction mixture was quenched with acetic
acid and MeOH/H2O. A solution briefly ensued from which
the desired product precipitated on stirring. Isolation at this
stage is ill-advised, however, since the solid product is
contaminated with ca. 20 wt % of salts. Instead, the reaction
mixture is distilled to one-half volume under vacuum and
then partitioned between methylene chloride and H2O.
Finally, the CH2Cl2 is removed in vacuo and replaced with
IPA from which the product precipitates as a colorless solid.
This process provided reproducible yields in the 85% range
on up to 175-kg input. Although suffering from the need
for a cryogenic setup, the chemistry is robust, reproducible,
and easily carried out on any scale. Our process is depicted
in Scheme 2. Recently, the Merck group has reported a
similar method.5,6
Much effort went into the development of a scalable
procedure for the generation of kilogram quantities of a
3-metallopyridine to be used in a transition metal-catalyzed
cross-coupling reaction to produce the desired carbon
framework. 3-Pyridyllithium has been known3 for many
years. Gilman had generated it in diethyl ether or petroleum
ether by a host of halogen-metal exchange procedures at
-20 to 0 °C, but only in modest yield.3 He suggested that
the earlier failures4 of these methods could be attributed to
the higher temperatures at which the reactions were run,
which allowed the pyridyllithium as it was formed to react
further with reaction byproducts and substrate. Early experi-
ments in the Dow laboratories had demonstrated an apparent
method to stabilize 3-pyridyllithium. If the species was
generated cold in predominately hydrocarbon solvent with
a small amount of diethyl ether present, a thick green-gray
slurry could be obtained. Although never characterized, this
precipitate is thought to be an ether solvate of an agglomer-
ated anionic pyridine species. It could be converted to
diethyl-3-pyridyl borane on reaction with commercially
available diethylmethoxy borane (DEMB), but the reaction
was somewhat capricious even on modest scale. However,
when one substitutes methyl tert-butyl ether for diethyl ether
at a 1.3-1.7 molar ratio relative to 3-bromopyridine and pays
very careful attention to reaction temperature, running
cryogenically at -40 to -50 °C, the reaction is very well
behaved. In fact, we determined during our development
work that the product of the metal-halogen exchange was
stable for at least 7 h at -45 °C, and no yield erosion was
observed in the generation of the transmetalated product. This
was a very significant finding since the initial charge of
n-butyllithium to the ether-containing hexane solvent is
exothermic and both the lithium-halogen exchange and the
The key Suzuki coupling reaction, shown in Scheme 3
performed well on the pyridyl borane and the bromosulfone
from the outset. As had been demonstrated previously, we
initially chose to use a polar variant, employing water and
THF as solvent, sodium hydroxide as base, and tetrakis-
(5) Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002, 4285.
(6) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen, R.
D.; Reider, P. J. J. Org. Chem. 2002, 67, 5394.
(4) Banner, I. M.S. Thesis, Iowa State College, Ames, Iowa, 1939.
386
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Vol. 7, No. 3, 2003 / Organic Process Research & Development

Scheme 3
environment is more hostile with stronger base and the ready
miscibility of water with the solvent. A nonpolar Suzuki
variant has since been reported.7 Another significant change
that produced this, our optimized final procedure, was to use
methane sulfonic acid for the salt formation in the isolation
of the product, allowing the precipitation to be conducted
under essentially anhydrous conditions. This final process
was scaled directly from laboratory glassware to 215 kg input
of bromosulfone, providing reproducible yields of 92-96%
of +98% quality product.
We had initially hoped that isolation of the methane
sulfonate salt would have another operational advantage as
well. The next step in the process is a selective catalytic
hydrogenation of the pyridine ring under pressure. We knew
that stainless steel autoclaves would not be compatible with
chloride counterion but thought that methane sulfonate would
be acceptable. During development in Paar bottles, initial
use of Adam’s catalyst (PtO2) followed by Pt/C cleanly
reduced the pyridine ring, activated as a salt; however,
relatively high temperatures were required (60-100 °C),
depending on the catalyst employed. We examined reduction
of the methane sulfonate salt of the biaryl and were quite
surprised to determine that methane sulfonic acid, under the
somewhat forcing conditions required for this hydrogenation,
attacked 316 stainless, as determined by iron content of the
product solution from a small autoclave run. We would
therefore strongly adVise against the reduction of methane
sulfonate salts in stainless steel autoclaVes.
Phosphate counterion is compatible with stainless steel
autoclaves, although its use required the addition of several
unit operations to the process. Thus, the Suzuki product could
be converted to the free base form, extracted into ethyl
acetate, and then extracted into a dilute aqueous phosphoric
acid solution as feedstock for the reduction. Unfortunately,
all attempts to crystallize the phosphate salt of the Suzuki
product met with failure, and this somewhat circuitous route
had to be employed. In the workup, a dilute phosphoric acid
solution of the secondary amine is neutralized and the product
extracted into methylene chloride. This extraction is very
tedious as the amine shows appreciable water solubility
below pH 12. However, at the high pH, di- and tri-basic
sodium phosphate begin to precipitate. To avoid the phos-
phate precipitation problem, it is critically important to
neutralize with potassium, and not sodium hydroxide. The
reduction was then telescoped into the classical resolution,
which was run as originally described.1,2 It provided reason-
ably good upgrading in acceptable recovery. Thus, without
isolation, the secondary amine phosphate was converted to
the free base and reacted with L-tartaric acid in aqueous
methanol. Crystallization provided directly the desired dia-
stereomeric tartrate salt between 65% and 81% de, as
measured by chiral HPLC on the free base. From the lower
de’s it required two recrystallizations to achieve ca. 95%
de, while from the higher initial de’s only one recrystalli-
zation sufficed; however, either way the yield is 80-85%
of the possible 50%, i.e., 40-43% from Suzuki product
hydrochloride 6, as overall recovery and quality appeared
(triphenylphosphine) palladium (tetrakis) as catalyst.2 We first
examined the use of other palladium sources, but heteroge-
neuous palladium was ineffective for this reaction. Reactions
were conducted at 65-67 °C for 8-12 h. For efficient
conversions a phase transfer catalyst was also required; we
used tetrabutylammonium bromide (TBAB) at the extremely
high loading of 35 mol %, and although this contributed little
to the cost, it interfered with the isolation of clean coupled
product (vide supra). We initially examined tetrakis loading,
as the described procedure used 5 mol % of the palladium
catalyst, and reported a yield of 84%. A catalyst turnover
rate of only 20 would be unacceptable on scale, given both
the high cost of tetrakis and its high molecular weight (1155.6
g/mol). We successfully decreased catalyst loading with no
yield erosion to 3.6 mol %, but unfortunately, this was the
lower limit for a successful conversion. At this catalyst
loading, though, a 1000 mol coupling to produce 240 kg of
product would still require some 40 kg of catalyst. Neverthe-
less, with a robust procedure in hand that was operationally
straightforward and provided reproducible yields in the 80%
range, the process was readied for eventual scale-up.
As noted, our lab runs were plagued in the early going
by product quality issues.
Although the product could be directly crystallized after
an aqueous partition, given the high TBAB requirement,
product isolated in this fashion tended to be contaminated
with varying amounts of the phase-transfer catalyst. This
problem, though, was fairly easily solved with a simple acid-
base extractive workup, and the clean hydrochloride salt
could be precipitated from 10% methanolic ethyl acetate by
the addition of 1.0 equiv of concentrated hydrochloric acid.
Despite the shortcoming of higher than desirable tetrakis
loading, this workup was used together with the previously
described reaction conditions on scales ranging up to 225
kg of bromosulfone, affording reproducible yields (typically
in the 80% range) of 98+% quality biaryl hydrochloride.
However, we were compelled by cost issues to continue
to examine variants of the Suzuki coupling and, in conjunc-
tion with another project also featuring a palladium-catalyzed
cross-coupling reaction, are pleased to report that the tetrakis
catalyst-loading issue has been, for the most part, resolved.
Thus, if the cross-coupling reaction is conducted under
nonpolar conditions, employing toluene as solvent in a two-
phase system with water and employing carbonate as the
base, it is possible to significantly reduce catalyst loading,
not only of the tetrakis but also of the TBAB. The reactions
were run at about 20 °C higher temperature (83-87 °C) than
that of the polar procedure, but tetrakis loading was optimized
at 0.7 mol % and TBAB at 9 mol %. We believe that these
nonpolar conditions offer some protection to the catalyst and
the organic reagents, which can be safely sequestered away
in the toluene phase. In the THF procedure, doubtless the
(7) Paetzgold, E.; Oehme, G. J. Mol. Catal. A: Chem. 2000, 69.
Vol. 7, No. 3, 2003 / Organic Process Research & Development
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387

Scheme 4
not to be interdependent. The complete series of transforma-
tions yielding resolved penultimate secondary amine from
Suzuki product is depicted below in Scheme 4.
difficult to separate from final product, and minimization of
its formation was tantamount to the success of the project.
Likewise, it became again necessary to free the substrate
from the tartaric acid counterion prior to conducting the
procedure since in the presence of tartaric acid unacceptable
quantities of the dimeric structure 19 ensue.
Although the Sonneson group claimed to have success-
fully introduced the propyl group via a variant of the
procedure first described by Maryanoff,8 using triacetoxy-
borohydride and propionaldehyde in ethylene dichloride, on
scale we observed under the reaction conditions that sig-
nificant amounts of chloroethylated product 17 was obtained
as well, with the solvent apparently competing effectively
with propionaldehyde for substrate.
Originally, we had isolated OSU 6162 free base and in a
separate step it was converted to the salt. The final procedure
that we chose for the pilot-plant runs, however, telescoped
the free base generation with the salt formation. Thus, after
the propylation workup, which involved simple aqueous
partition, the solvent was swapped for an EtOAc/EtOH
mixture, and an equivalent of anhydrous HCl in EtOAc was
added. The pure HCl salt begins to precipitate midway
through the addition. It is interesting to note that secondary
amine tartrate of only ca. 93% de could be carried on to
final OSU 6162 on the order of 99% ee, demonstrating that
enantiomeric enrichment accompanies the final crystalliza-
tion. It was, however, not possible to obtain usable second
crops. The overall yield for this final set of transformations
from the secondary amine free base is in the 70-75% range.
However, in conjunction with some other work, we had
occasion to employ the Gribble procedure9 as a viable option
for pilot-scale batch reductive aminations. It is, in fact, an
excellent method for this chemistry. Cyanoborohydride
procedures are frequently used on lab scale for these
transformations, but the resultant cyanide cleanup problems
in batch reactors are problematic. The Gribble procedure,
which is postulated to generate an aldhehyde or aldehyde
equivalent in situ by the action of sodium borohydride on a
carboxylic acid, is both clean and high-yielding. It may be
run both neat, with the carboxylic acid as solvent, or with
THF as cosolvent. Thus, our amine free base substrate 8 in
THF was treated with an excess of propionic acid, and an
excess of sodium borohydride was added portionwise via
shot loader at 0 to -10 °C. The mixture is heated to a gentle
reflux to complete the reaction. It is of critical importance
to conduct the borohydride addition portionwise. We isolated
and characterized borane adduct 18 as a THF solvate from
laboratory runs in which the borohydride addition was
conducted too quickly. This impurity proved extremely
Conclusions
A relatively efficient method of preparation of the clinical
candidate OSU 6162 has been demonstrated on scale. It in-
volves as the key construction a soluble palladium-catalyzed
Suzuki coupling. An efficient method of generating and
transmetallating unstable 3-pyridyllithium is also described.
The overall final process is shown in Scheme 5. It provides
clinical quality OSU 6162 in overall 33-47% yield from
1,3-dibromobenzene, or in its final form, in 46-61% yield,
3-bromomethyl sulfone, taking into account the required
classical resolution. Although long in unit operations, the
(8) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett.
1990, 5595.
(9) Gribble, G. W.; Jasinski, J. M.; Pelicone, J. T.; Panetta, J. A. Synthesis
1978, 776.
388
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Vol. 7, No. 3, 2003 / Organic Process Research & Development

Scheme 5
Table 1
process is straightforward and provides workable yields of
high-quality material. It supplied over 35 kg of bulk drug in
one small and one large pilot-plant campaign in just over a
year’s elapsed time.
GC procedures Samples are quenched into aqueous NaOH and
EtOAc. 1.0 µL of the organic phase is injected.
column:
temperature:
detection:
15 M DB-1
50 °C, 10 °C/min program
FID
retention times: dibromobenzene - 6.5 min
3-bromothioanisole - 9.1 min
Experimental Section
Reagents were purchased from commercial suppliers and
used without purification. H NMR spectra were recorded
1,3-(thiomethyl)bezene - 11.3 min
1
at 300 or 400 MHz on Brucker instruments in CDCl3, D2O,
or DMSO-d6, and values are reported as parts per million
downfield. 13C NMR spectra were recorded at 100 MHz on
a Brucker instrument in CDCl3 or D2O, and values are
reported as parts per million downfield.
indicated the product to be of ca. 90% quality. The methyl-
3-bromothioanisole was used directly in the next step.
Methyl-3-bromophenyl Sulfone (4). A clean, dry, 400-L
stainless steel reactor under an inert atmosphere was charged
with 37 kg (164 mol corrected) of crude 3- bromothioanisole
and 166 kg of glacial acetic acid. The mixture was heated
to 32 °C and treated cautiously over 45 min with 19.9 kg
(161 mol) of 27.5% hydrogen peroxide. An additional 19.9
kg (161 mol) of 27.5% hydrogen peroxide was then added,
and the reaction was heated to 92 °C for 18 h. It was cooled,
and a sample was analyzed by TLC (see Table 2) for sulfone
and sulfoxide content, and by starch iodide paper for the
presence of peroxides (none detected). The reaction mixture
was then concentrated under reduced pressure to ca. 60 L
and azeotroped with 132 kg of isopropyl alcohol (IPA). An
additional 70 kg of IPA was charged, and the reaction
mixture was heated to 85 °C to dissolve the solids. It was
then cooled to 16 °C and stirred for 8 h, and the product
3-Bromothioanisole (3). A clean, dry, 400-L stainless
steel reactor under an inert atmosphere was charged with
40.0 kg (170 mol) of 1,3-dibromobenzene and 54 L of
N-methylpyrrolidinone (NMP). Solid sodium thiomethylate
(12.0 kg, 171 mol) was then added via shot loader in 1.0-kg
portions over ca. 2 h, keeping the temperature below 50 °C.
The reaction mixture was heated to 64 °C for 2 h, at which
time GC analysis (see Table 1) indicated that it was about
90% complete. It was then cooled to 20 °C and quenched
by the addition of 4.88 kg (61 mol) of 50% NaOH and 56
L of water. After 10 min of stirring, the reaction mixture
was diluted with 66 kg of hexane, and the phases were
separated. The organic phase was washed with 50 L of water
and concentrated under vacuum to ca. 37 L. GC analysis1
Vol. 7, No. 3, 2003 / Organic Process Research & Development
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389

Table 2
Table 4
TLC conditions: reaction mixtures are applied directly to the
plate and blown dry under a stream of nitrogen
TLC conditions: Reaction mixtures are applied directly to the
plate and blown dry under a stream of nitrogen.
Solids are dissolved in CH2Cl2 and the
plate:
EM silica gel 60 F254
solution applied to the plate.
solvent system: 1:1 EtOAc:heptane
plate:
EM silica gel 60 F254
visualization:
Rf values:
UV
solvent system: 90:9:1 ) CH2Cl2:MeOH:NH4OH
sulfone (4) - 0.2
visualization:
Rf values:
UV
intermediate sulfoxide (9) - 0.4
starting material (3) - 1.0
product (6) - 0.5
of tetra-n-butylammonium bromide (TBAB), 9.13 kg (62.1
mol) diethyl-3-pyridyl borane, and 103 kg of tetrahydrofuran
(THF). The slurry was stirred for 20 min and cooled to 1
°C, and 12.75 kg (159 mol) of 50% NaOH was added.
Finally, 2.9 kg (2.47 mol) of tetrakis(triphenylphosphine)
palladium was added portionwise, and the reaction mixture
was stirred for 1 h at 4 °C. The reaction mixture was heated
to 66 °C and stirred for 2 h, at which time TLC analysis
(see Table 4) indicated that the reaction was complete. The
mixture was cooled to 17 °C and stirred for 14 h, and the
THF was distillatively replaced with 110 L of EtOAc. The
reaction mixture was carefully acidified to ca. pH ) 1 with
80 L of 10% aqueous HCl, and the phases were separated.
The organic phase was extracted with an additional 35 kg
of 10% HCl. The combined aqueous phase was extracted
with 40 L of EtOAc, and the combined organic phase was
labeled and reserved for recovery of soluble palladium
wastes. The aqueous phase was then treated with 65 L of
EtOAc, and the pH was adjusted to 7-8 by the careful
addition of 23.5 kg of 50% NaOH. The phases were
separated, and the aqueous phase was extracted two more
times with 65-L portions of EtOAc. Since some product
remained in the aqueous phase, the pH was readjusted to
11-12 by the addition of another 1.0 kg of 50% NaOH,
and another extraction with an additional 50 L of EtOAc
was conducted. The organic extracts were then concentrated
under reduced pressure to ca. 40 L, diluted with an additional
40 L of EtOAc and 8 L of MeOH, cooled to 10 °C, and
treated with 6.00 kg (57.5 mol) of 35% HCl. The slurry was
then concentrated to 20 L under reduced pressure and stirred
a total of 18 h at -4 °C. The product was isolated by
filtration. The crystals were washed with cold EtOAc, and
the cake was dried under a stream of warm nitrogen. Yield
was 11.44 kg (89.6%).
Methyl-3-(3-pyridinyl)benzenesulfone Methanesulfonate,
Nonpolar Variant (15b). A clean, dry 4000-L glass-lined
steel reactor under an inert atmosphere was charged with
215 kg (915 mol) of methyl-3-bromophenyl sulfone, 26.2
kg (78.8 mol) of tetra-n-butylammonium bromide (TBAB),
134 kg (912 mol) of diethyl-3-pyridyl borane, and 1204 L
of toluene. The slurry was stirred for 20 min, and 798 kg
(2714 mol) of 47% aqueous potassium carbonate diluted with
430 L of water was added. Finally, a slurry of 7.1 kg (6.1
mol) of tetrakis(triphenylphosphine) palladium in 100 L of
toluene was added. The reaction mixture was heated to 84
°C and stirred for 12 h at which time HPLC analysis (see
Table 5 indicated that the reaction was complete. It was
cooled to 21 °C, stirred for 3 h, and filtered. The phases
were separated. The organic phase was extracted first with
2200 L of 3.7% aqueous hydrochloric acid and then
Table 3
TLC conditions:
reaction mixtures are applied directly to the
plate, solids are dissolved in EtOAc and
applied, and then blown dry under a
stream of nitrogen
EM silica gel 60 F254
1:1 EtOAc:heptane
plate:
solvent system:
visualization:
Rf values:
UV
Suzuki reagent (14) - 0.5
was filtered and washed with fresh IPA. The product was
dried under a stream of 40 °C nitrogen to 28.65 kg (122
mol, 71.8% yield for two steps). H NMR (CDCl3): 3.07
(3H, s), 7.47 (1H, t), 7.79 (1H, d), 7.89 (1H, d), 8.10 (1H,
m) ppm, 13C NMR (CDCl3): 44.49, 123.39, 125.97, 130.45,
130.95, 136.83, 142.41 ppm.
1
Diethyl-3-pyridyl borane (14). A clean, dry, 4000-L
glass steel reactor under an inert atmosphere was charged
with 156 kg of methyl-tert-butyl ether (MTBE) and 815 kg
of hexane. It was then cooled to -28 °C, and 289 kg (1111
mol) of 24.2 mol % n-butyllithium in hexane was added.
The reaction mixture was further cooled to -44 °C, and 175
kg (1107 mol) of 3-bromopyridine in 97 L of hexane was
added over 3 h, keeping the temperature below -40 °C. With
continued cooling, 119 kg (1195 mol) of diethylmethoxybo-
rane (DEMB) was added to the thick slurry over 8 h, keeping
the temperature below -32 °C. After 0.5 h of stirring, the
thick reaction mixture was quenched by the addition of 66.2
kg (1106 mol) of glacial acetic acid, and 97 kg MeOH and
97 L of H2O were added. The solution was stirred for 2 h at
11-15 °C at which time precipitation was evident. It was
then carefully concentrated under reduced pressure to ca. 700
L and diluted with 1706 L of methylene chloride and 1116
L of water. The phases were separated, and the aqueous phase
was extracted with an additional 613 L of methylene chloride.
The combined organic phase was concentrated under reduced
pressure to ca. 500 L. A 677-L portion of IPA was then added
and the mixture again concentrated to ca. 500 L under
reduced pressure. It was cooled to -25 °C, stirred for 2 h,
and filtered. The product solids were washed with fresh, cold
IPA and dried at 40 °C under a stream of nitrogen. The yield
was 122.4 kg, 75%. Material was single zone by TLC (see
Table 3). 1HNMR (CDCl3): 0.51 (6H, t), 0.66 (4H, m), 7.23
(1H, t), 7.58 (1H, s), 7.72 (1H, d), 8.01(1H, d) ppm. 13C
NMR (CDCl3): 9.20 (m), 14.45 (bs), 123.44, 140.85, 143.81,
149.13, 155.27 (bs) ppm.
Methyl-3-(3-pyridinyl)benzenesulfone Hydrochloride,
Polar Variant (15a). A clean, dry 400-L Hastalloy reactor
under an inert atmosphere was charged with 14.5 kg (61.7
mol) of methyl-3-bromophenyl sulfone, 7.26 kg (21.8 mol)
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Table 5
Table 7
HPLC conditions: One drop of reaction mixture is added
to 5 mL of acetonitrile.
HPLC conditions: A 6.2 mg sample of the tartrate is partitioned
between 3 mL 1 N NaOH and 3 mL of
CH2Cl2. The organic phase is concentrated
under a stream of nitrogen and taken up
column:
Luna C-18 (4.6 mm × 250 mm)
injection volume: 10 µL
mobile phase:
flow rate:
in 3 mL of mobile phase for analysis.
60:40 ) acetonitrile:0.1 M ammonium acetate
01.0 mL/min
column:
Chiracel OD-H (4.6 mm × 250 mm)
injection volume: 10 µL
detector:
retention times:
229 nm
sulfone (4) - ca. 6.0 min
product (6) - ca. 3.7 min
mobile phase:
flow rate:
800:200:2 ) heptane:ethanol:diethylamine
0.8 mL/min
detector:
267 nm
retention times:
desired enantiomer of (8) - ca. 13 min
undesired enantiomer of (8) - ca. 15 min
Table 6
TLC conditions: Reaction mixtures are applied directly to the
plate and blown dry under a stream of
and the mixture was cooled during the adjustment of the pH
to between 12 and 13 with about 50 L of 50% potassium
hydroxide. The phases were separated, and the aqueous phase
was extracted with 2 × 25-L portions of methylene chloride.
The combined organic phase was concentrated under reduced
pressure to ca. 15 L. Methanol (87 L) was added, and the
mixture was reconcentrated to ca. 15 L. This was treated
with a solution of 6.05 kg (40.3 mol) of L-tartaric acid in 40
L of methanol. The volume was adjusted to 55 L, and the
mixture was heated to 70 °C for 30 min. Water (23 L) was
added, and the solution was cooled with stirring to 10 °C to
induce crystallization. The slurry was stirred for 8 h, and
the solids were isolated by filtration, washed with 10 L of
1:1 H2O:MeOH, and dried under a steam of nitrogen at 40
°C. The yield was 7.0 kg of material, the free base component
of which assayed at 67% ee (see Table 7). This lot was
combined with a lot similarly prepared, and the 17.6 kg total
of ca. 66% de methyl-3(3-piperdinyl)benzenesulfone tartrate
was charged into a clean, dry, inert 400-L Hastalloy reactor.
Methanol, (79 kg) and water (46 L) were then added, and
the mixture was heated to 66 °C. After 30 min at this
temperature, the solution was cooled to 62 °C and seeded.
It was further cooled over a 3-h period to 10 °C, and the
slurry was stirred for 17 h. The solids were filtered, washed
with 15 kg of MeOH, and dried under a stream of warm
nitrogen to 12.7 kg of material, the free base component of
which assayed at 83.7% ee (see Table 7). The crude methyl-
3(3-piperdinyl)benzenesulfone tartrate was recrystallized yet
again from 68 kg of MeOH and 40 kg of H2O, affording
9.73 kg of product, the free base component of which assayed
at 93% ee (see Table 7). This material was successfully use-
tested in the final propylation/salt formation prior to proceed-
ing.
nitrogen. Solids are dissolved in CH2Cl2
and the solution applied to the plate.
plate:
EM Silica gel 60 F254
90:9:1) CH2Cl2:MeOH:NH4OH
UV and I2
solvent system:
visualization:
Rf values:
product (7) - 0.2
starting material (6) - 0.5
re-extracted with an additional 630 L of 3.7% aqueous
hydrochloric acid. The combined aqueous extracts were
treated with 860 L of methylene chloride and cooled as the
pH was adjusted to 12 with 50% aqueous sodium hydroxide.
The phases were separated, and the aqueous phase was
extracted with two more 860-L portions of methylene
chloride. The combined organic phase was treated with 200
L of ethyl acetate, transferred to a clean, dry 4000-L glass-
lined steel tank and concentrated under reduced pressure to
400 L of final volume. Ethyl acetate (1500 L) was added,
and the mixture was then concentrated under reduced
pressure to 900 L. Methanol (110 L) was added, and the
solution was cooled to 7 °C and treated with 87.9 kg (916
mol) of methane sulfonic acid. The slurry was stirred for 17
h at 5 °C and filtered, and the cake was rinsed with 120 L
of cold ethyl acetate. Drying with 40 °C nitrogen yielded
278.3 kg (92.5%). 13C NMR (CDCl3): 38.81, 43.65, 126.32,
127.96, 128.77, 131.37, 133.66, 135.52, 138.86, 140.13,
140.57, 140.90, 145.31 ppm.
Methyl-3-(3-piperdinyl)benzenesulfone Tartrate (16).
A clean, dry 400-L glass reactor under an inert atmosphere
was charged with 160 L of EtOAc and 12.3 kg (37.4 mol)
of methyl-3-(3-pyridinyl)benzenesulfone hydrochloride. This
was treated with 15.5 kg of sodium bicarbonate dissolved
in 161 L of H2O, and the phases were separated. The aqueous
phase was extracted two more times with 80-L portions of
EtOAc, and the combined organic phase was then extracted
with 4 × 15 kg portions of 16.75% aqueous phosphoric acid.
A clean, dry, inert 120-L stainless steel autoclave was
charged with 2.91 kg of 5% Pt/C, and the phosphoric acid
solution of Suzuki-coupled product from above was rinsed
in with 5 L of 16.75% aqueous phosphoric acid. The mixture
was hydrogenated at 98 °C under approximately 60 psi of
H2 for 18 h, at which time TLC analysis (see Table 6)
indicated that the reaction was complete. The catalyst was
filtered off, and the cake was washed with 5 × 20 L portions
of warm, dilute phosphoric acid. The hydrogenate was
charged to a clean, dry, 400-L glass-lined steel reactor under
an inert atmosphere. Methylene chloride (28 L) was added,
Methyl-3-(3-N-methylpiperdinyl)benzenesulfone, Hy-
drochloride (OSU 6162, 1). A clean, dry, 1200-L glass
reactor under an inert atmosphere was charged with 18.0 kg
(46.2 mol) of resolved (97% de by HPLC, see Table 7)
methyl-3(3-piperdinyl)benzenesulfone tartrate and 150 L of
methylene chloride. The mixture was cooled during the
addition of 250 L of 3.3% aqueous NaOH, and the phases
were separated. The aqueous phase was extracted with an
additional 150 L of methylene chloride, and the combined
organic phase was treated with 75 L of THF and concentrated
to ca. 40 L. The concentrate was azeotroped in portions with
198 kg of THF to a final volume of ca. 40 L, and the volume
was adjusted to 140 L with additional THF. The solution
Vol. 7, No. 3, 2003 / Organic Process Research & Development
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391

Table 8
Table 9
HPLC conditions:
10 mg of the product is dissolved in 2 mL
of ethanol, and 8 ml of hexane is added.
CHIRALPACK AS (4.6 mm × 250 mm)
10 µL
TLC conditions: Reaction mixtures are quenched into saturated
aqueous bicarbonate/EtOAc and the EtOAc
column:
phase spotted. Solids are dissolved in CH2Cl2,
injection volume:
mobile phase:
flow rate:
detector:
retention times:
and the solution is applied to the plate.
975:25:1 ) hexane:methanol:diethylamine
plate:
EM silica gel 60 F254
90:9:1) CH2Cl2:MeOH:NH4OH
UV
0.6 mL/min
267 nm
PNU-100010 (wrong enantiomer) - ca. 20 min
OSU 6162 (1) - ca. 22 min
solvent system:
visualization:
Rf values:
starting material (8) - 0.3
product (1) - 0.6
by filtration. The cake was washed with 10 L of EtOAc and
dried under a stream of warm nitrogen, leaving clinical
quality OSU 6162 (1), 10.45 kg (71.6% yield), which passed
all specifications. Chiral HPLC assay (see Table 9) showed
it to be >99% single enantiomer. 1H NMR (DMSO-d6): 0.90
(3H, t), 1.67-1.84 (3H, m), 1.94 (2H, bs), 2.08 (1H, q),
2.89-3.01 (3H, m), 3.17 (1H, q), 3.18 (3H, s), 3.38-3.68
(2H, m), 7.67 (2H, m), 7.85 (2H, m), 11.15 (1H, bs). 13C
NMR (DMSO-d6): 11.40, 16.80, 22.64, 29.33, 39.51, 43.87,
51.39, 55.73, 58.18, 125.82, 126.10, 130.23, 132.87, 141.64,
143.37 ppm.
was cooled to -5 °C and treated with 25.0 kg (338 mol) of
propionic acid, and then 5.10 kg (135 mol) of NaBH4 was
added portionwise over 2 h via shot loader, keeping the
temperature below -5 °C. The reaction mixture was warmed
to 25 °C, stirred for 1 h, and heated to 63 °C. The temperature
was maintained at 63 °C for 14 h at which time TLC analysis
(see Table 8) indicated that the reaction was complete. The
mixture was cooled to 20 °C, carefully quenched with 220
L of 8.5% aqueous sodium bicarbonate, after which 200 L
of EtOAc was added. The phases were separated, and the
organic phase was extracted sequentially with 100 L of 8.5%
aqueous sodium bicarbonate, 90 L of water, and 160 L of
saturated aqueous sodium chloride. The combined aqueous
phase was back-washed with 2 × 120 L portions of EtOAc.
The combined organic phase was concentrated to ca. 130 L
and then azeotroped with an additional 100 L of EtOAc to
a final volume of ca. 130 L. Anhydrous ethanol, 12 L, was
added followed by 28.8 kg (50.8 mol) of a 6.9 wt % solution
of anhydrous HCl in EtOAc. The resulting slurry was stirred
at 10 °C for 1.5 h, and the crystalline product was isolated
Acknowledgment
We thank J. R. Gage for helpful discussions, B. G.
Conway and D. E. Ruimveld for hydrogenation support, W.
R. Perrault and J. P. Scholl for chiral assay support, and D.
J. Knoechel for process safety data.
Received for review December 20, 2002.
OP025620U
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