Selection and scale-Up evaluation of an alternative route to (-)-(3R,4R)-1-Benzyl-4-(benzylamino)piperidin-3-ol

Article abstract of DOI:10.1021/op300174w

An efficient, scalable synthesis of (-)-(3R,4R)-1-benzyl-4-(benzylamino) piperidin-3-ol (4) is described. Reduction of the pyridinium salt prepared from pyridine and benzyl chloride generated the corresponding tetrahydropyridine derivative. A two-stage epoxidation, followed by ring-opening of the epoxide with BnNH₂, established the regiochemistry of the amino alcohol and served to set the trans-relationship between the amine and the hydroxyl group. The resulting racemic intermediate was then resolved by salt formation with (R)-O-acetyl mandelic acid. The process produced the O-acetyl mandelic acid salt of (-)-4 in 27% overall yield from benzyl chloride.

Full text of DOI:10.1021/op300174w

Article
pubs.acs.org/OPRD
Selection and Scale-Up Evaluation of an Alternative Route to
(−)-(3R,4R)‑1-Benzyl-4-(benzylamino)piperidin-3-ol
Ian S. Young,* Adrian Ortiz, James R. Sawyer, David A. Conlon, Frederic G. Buono, Simon W. Leung,
Justin L. Burt, and Eric W. Sortore†
Chemical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States
ABSTRACT: An efficient, scalable synthesis of (−)-(3R,4R)-1-benzyl-4-(benzylamino)piperidin-3-ol (4) is described.
Reduction of the pyridinium salt prepared from pyridine and benzyl chloride generated the corresponding tetrahydropyridine
derivative. A two-stage epoxidation, followed by ring-opening of the epoxide with BnNH2, established the regiochemistry of the
amino alcohol and served to set the trans-relationship between the amine and the hydroxyl group. The resulting racemic
intermediate was then resolved by salt formation with (R)-O-acetyl mandelic acid. The process produced the O-acetyl mandelic
acid salt of (−)-4 in 27% overall yield from benzyl chloride.
and coupling partner 2 is generated from bis-benzyl derivative
(−)-4. 3,4-Disubstituted piperidine (−)-4 is the compound of
interest in this communication.
INTRODUCTION
■
Lung cancer is responsible for over one-third of cancer related
deaths in the United States, with the non-small cell variant
being a particularly aggressive form. Treatments that prolong
the life of those stricken with this disease are of the utmost
importance and, as a result, are being actively investigated by
the pharmaceutical industry. BMS-690514 (1) is a potential
therapeutic agent for the treatment of lung and other cancers.1
From a retrosynthetic perspective, compound 1 can be
dissected to protected piperidine 2 and pyrrolotriazine 3, the
union of which is realized by an SN2 displacement of the
activated primary alcohol (Figure 1). Compound 3 is derived
from chloro-substituted pyrrolotriazine 6 and m-anisidine (5);
The current large scale synthesis of piperidine (−)-4 features
the ring expansion of pyrrolidinol 9, which is derived from (R)-
pyroglutamic acid (7).2 The overall process requires seven steps
and proceeds in 22% overall yield (Figure 2). Although this
strategy has been used to prepare greater than 200 kg of
piperidine (−)-4, many of the transformations are operationally
laborious. The preparation of (−)-4 requires significant plant
time, leading to decreased throughput and increased
production costs. Due to the need for large quantities (>100
kg) of 1, a more efficient synthesis of (−)-4 was desired.
As previously reported,3 four alternative syntheses of
compound (−)-4 were accomplished on lab scale (Figure 2).
We began to evaluate the metrics/(dis)advantages of each
strategy to select a route for further development. The initial
sequence considered (route A, Figure 2) set the absolute and
relative stereochemistry through asymmetric hydrogenation of
enolized β-ketoester 10, and a Curtius rearrangement installed
the second requisite nitrogen of 11. This route produced cyclic
carbamate 11 in high overall yield (68%) and in short order (3
steps). Carbamate 11 has the potential to serve as an alternative
protecting group to those currently used (Boc, Bn) during the
coupling,4 although the API step deprotection would have to be
redeveloped. Alternatively, 11 could be converted to 4 by a two
step process (hydrolysis of carbamate and subsequent
benzylation). While this work was being conducted, the cost
and availability of the hydrogenation ligand 12 were of concern.
Route B utilized material from the chiral pool and featured
ring expansion5 of a 2-deoxy-D-ribose derived bis-amine 14.
This strategy was shorter than the current route (5 vs 7 steps)
but produced the desired target in only 15% overall yield
(>99.9% ee). The key rearrangement to produce (−)-4 was low
yielding and would require substantial optimization. The
rearrangement was complicated by the observation that each
Figure 1. Retrosynthesis of BMS-690514 (1) to yield the intermediate
of interest (4).
Received: June 29, 2012
Published: September 6, 2012
© 2012 American Chemical Society
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Figure 2. Current route to piperidine (−)-4 and evaluation of alternative strategies. FGI = functional group interconversion; OAMA = (R)-O-acetyl
mandelic acid.
anomer of 14 displayed differing behavior upon subjection to
catalytic hydrogenolysis. One anomer converted to the desired
product (4) more rapidly (1−2 h), and if this anomer was
subjected to the extended reaction times (4.5 h) required to
convert the other anomer to 4, substantial product N-
debenzylation occurred. To overcome this, the anomers had
to be separated prior to rearrangement. Another concern was
the necessity to purify the polar intermediates by chromatog-
raphy, as anomeric mixtures at each stage rendered isolation by
crystallization difficult. Route C also utilized 2-deoxy-D-ribose
(13) as a feedstock, from which a bis-mesylate intermediate was
prepared. Double displacement of the mesylates with BnNH2
induced closure to piperidine 17. Further functional group
manipulations6 installed the epoxide of 18, which was
regioselectively opened (>20:1) with BnNH2 in the presence
of a lithium salt.7 Overall, seven steps were required to produce
(−)-4 in 10% yield (>99.9% ee), with inefficient epoxide
formation (26%) being the major contributor to the low overall
yield. Instability of the bis-mesylate intermediate and difficulties
encountered during purifications were also areas of concern.
The final sequence considered (Route D) featured an
alternative synthesis of the epoxide (18) used in Route C,
albeit in racemic form (22).8 After opening with BnNH2, ( )-4
was produced in 50% yield (5 steps, unoptimized) from
inexpensive and readily available benzyl chloride (19) and
pyridine (20).9 After resolution with (R)-O-acetyl mandelic
acid (OAMA), the salt of 4 was obtained in 22% overall yield
(93.8% ee after salt break).10 Upon evaluating the scalability of
this sequence, we envisioned a reduction in the number of
operations through telescoping transformations. Challenges
associated with this route were that some intermediates were
identified to be oils and salt formation was necessary for
crystallization. Additionally, further resolution development
would be required to increase enantiomeric excess.
With four sequences available, we defined our criteria for
route selection: (a) a reduction in step count compared to the
current seven steps; (b) utilization of inexpensive starting
materials; and (c) a reduction in the total number of
operations. Based on the summaries in Figure 2, we deemed
that Route D had the greatest potential to meet these
requirements. Only five steps were required from inexpensive
pyridine and benzyl chloride, and the reactions on lab scale
were operationally simple to perform. Areas requiring further
study were identified during our lab scale campaign (lack of
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crystalline/isolable intermediates, and the requirement for
resolution optimization). Preliminary results during the lab
scale development of this route [fumaric acid salt of epoxide 22
for isolation, and (R)-O-acetyl mandelic acid for the resolution
of ( )-4 (44%, 93.8% ee)]10 served as a starting point for
addressing these issues. The following reports our findings and
optimizations upon performing this chemistry on scales
approaching 1 kg.
Scheme 2. Addition Modes Evaluated by Calorimetry for the
Reduction of Pyridinium Salt 23 and the 20 L Procedure
a
RESULTS AND DISCUSSION11
■
Although not discussed in our original communication,3
tetrahydropyridine 21 was prepared by the alkylation of
pyridine with benzyl chloride and subsequent reduction.12
The initial lab-scale procedure required slow addition of benzyl
chloride to neat pyridine at 120 °C to prevent a delayed
exotherm (Scheme 1). The resulting salt 23 was dissolved in
a
For A and B, values are for addition of 0.1 equiv of limiting reagent
(NaBH4 and 23, respectively).
3). In the reverse mode of addition [23 (0.25 mmol in ethanol)
to an ethanol solution of NaBH4 (2.5 mmol) (mode B, Scheme
Scheme 1. Preparation of Tetrahydropyridine 21 by Original
Lab Scale (o) and Proposed Modified (m) 20 L Procedures
methanol, and solid sodium borohydride was added portion-
wise to prevent excessive foaming. After workup, tetrahydro-
pyridine 21 was isolated by vacuum distillation. As a means to
alleviate the first issue (neat reaction conditions, 120 °C), we
evaluated the performance of this alkylation in toluene.
Although the precipitated product could be isolated by
filtration, the hygroscopicity of 23 limited the practicality of
this approach. We then considered the possibility of performing
the alkylation reaction in ethanol, as this would allow the
reduction to be performed in the same reactor without isolation
of salt 23. Experimentally, the reaction required 8−10 h at
reflux for complete consumption of benzyl chloride. A slight
excess of pyridine (7%) was utilized, as the presence of residual
benzyl chloride during the subsequent reduction led to
quaternization of reduction product 21. With an ethanolic
solution of 23 in hand, we began development of a scalable
sodium borohydride reduction.
During the original lab scale developments, solid sodium
borohydride (1.2 equiv) was added portionwise to a methanol
solution of salt 23 to minimize foaming/exotherm. It was
estimated that this addition would take 3−4 h on 20 L scale,
rendering this addition method impractical. To alleviate the
issue, we considered two protocols for reduction: 1) addition of
a basic, aqueous solution of sodium borohydride to the
alcoholic solution of 23; and 2) addition of the alcoholic
solution of 23 to a slurry of sodium borohydride in ethanol. It
was presumed that each of these alternatives would yield a dose
controlled reaction rate. Prior to scaling this reaction to 20 L,
we initiated a study of the reduction by calorimetry to identify
potential thermal events.
Figure 3. Heat flow versus time detected by isothermal reaction
calorimetry.
2)], the total heat detected was 464 J, with the exotherm being
self-sustaining for more than 140 min. There was also a
substantial increase in pressure within the calorimeter during
this mode of addition. The marked difference in heat evolution
(79 vs 464 J) resulted from the tertiary amine reduction
product13 (21) catalyzing the exothermic decomposition14 of
the remaining sodium borohydride (0.9 equiv). To validate this
theory, addition of a catalytic amount of tetrahydroypyridine 21
to a slurry of sodium borohydride in ethanol initiated violent
gas evolution, indicating that reverse addition of pyridinium salt
23 to NaBH4 was not feasible. Further lab scale optimization in
conjunction with calorimetry studies identified the addition of a
solution of NaBH4 (1.15 equiv) in aqueous NaOH (0.01 M)15
to an ethanol solution of 23 as a viable procedure for scale-up
(Scheme 2, 20 L procedure). For this process, the heat detected
by reaction calorimetry was 80 J and the adiabatic temperature
rise was estimated to be 104 °C. Upon implementation on 20 L
scale, addition of the NaBH4 solution over 4 h led to minimal
exotherm and allowed the reaction temperature to be
maintained below 20 °C.
Initially, the mode of addition (NaBH4 to 23 vs 23 to
NaBH4) was evaluated on the basis of heat evolution. Charging
an ethanol solution of sodium borohydride (0.25 mmol, 10 mol
%) to a solution of 23 (2.5 mmol) in ethanol at 10 °C (mode
A, Scheme 2) generated 79 J over a 6 min reaction time (Figure
With a process to safely produce tetrahydropyridine 21 on
scale, we turned our attention to improving the epoxide
formation sequence. For lab scale development, distilled 21 was
treated with NCS in the presence of TFA to form the
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chlorohydrins 24/25 (Scheme 3). The crude product was then
isolated and subjected to potassium carbonate (2.0 equiv) in
upon direct addition of fumaric acid to the refluxing epoxide
solution also needed to be addressed. Due to the insolubility of
fumaric acid in most organic solvents, slow addition of a
fumaric acid solution to the epoxide stream was not feasible.
After exploring a variety of mixed solvent systems, it was found
that fumaric acid was soluble in 11 volumes of 10:1 acetone/
water at reflux (higher ratios of water further increased fumaric
acid solubility but led to diminished recovery of the salt 26).
After reducing the temperature of the fumaric acid solution to
45 °C (the minimum temperature at which the fumaric acid
would remain soluble), seeds of 26 (10 mol %) were added.
The crude epoxide solution in 2-MeTHF (used instead of
MTBE for extraction of the epoxide) was then dosed at a rate
to control the crystallization. Salt 26 was obtained in 59% yield
(from benzyl chloride) with a purity of 94−96 LCAP (liquid
chromatography area percent, crude LCAP = 76−80). The
addition temperature of 45 °C was a key process parameter. If
the epoxide solution is added to the fumaric acid solution at
temperatures > 50 °C, a significant amount (up to 12%) of
byproduct (27) from epoxide opening by fumaric acid is
observed in the isolated product.
Scheme 3. Preparation of the Racemic Epoxide by Both
Original Lab Scale (o) and Modified 20 L (m) Methods
methanol to yield epoxide 22. For the 20 L campaign, the crude
tetrahydropyridine stream from reduction of pyridinium 23 was
used directly. A similar protocol for epoxide formation was
utilized, with the exception of the direct addition of 10 N
NaOH to the reactor once chlorohydrins formation was
complete. This removed the necessity for workup and isolation
of 24/25. It was necessary to charge 4.2 equiv of sodium
hydroxide to compensate for the acidic components [TFA
(1.25 equiv) and succinimide (1.2 equiv), leaving 1.75 equiv of
NaOH for reaction] present from chlorohydrin preparation.
After three telescoped steps, the crude epoxide 22 was extracted
into an organic solvent in preparation for salt formation/
crystallization with fumaric acid.
With the fumaric acid salt (26) in hand we were prepared to
evaluate epoxide opening and resolution on scale. For the lab
scale synthesis, fumaric acid was removed by basic washes to
yield epoxide 22, and then epoxide opening (LiCl, BnNH2,
CH3CN) proceeded with a high degree of regioselectivity
(>20:1)7c to yield ( )-4 (Scheme 5). Racemic 4 was
Scheme 5. Preparation of Racemic 4 and Resolution by Both
a
Original Lab Scale (o) and Modified 20 L (m) Methods
On lab scale, crude epoxide 22 was extracted into MTBE,
concentrated, and then redissolved in acetone. After heating
this solution to reflux, solid fumaric acid (1.0 equiv) was added
directly to the flask (Scheme 4). This led to rapid precipitation
Scheme 4. Preparation of Fumaric Acid Epoxide Salt 26 by
Both Original Lab Scale (o) and Modified 20 L (m)
a
Methods
a
FA = fumaric acid; OAMA = (R)-O-acetyl mandelic acid.
crystallized from toluene/heptane (85%) and then subjected
to the unoptimized resolution conditions [ethanol (anhydrous),
(R)-O-acetyl mandelic acid] to yield 28 (42%, 93.8% ee).10
Upon scaling this sequence to 20 L, our objectives were to
eliminate the isolation/crystallization of racemic 4 prior to
resolution, and improve both the recovery and enantiomeric
excess of isolated 28.
The epoxide opening conditions (LiCl, BnNH2, CH3CN)
used on lab scale to generate racemic 4 yielded similar results
on scales approaching 1 kg and were not modified. Further
development of the isolation/resolution of racemic 4 supported
the continued use of (R)-O-acetyl mandelic acid (29) in
alcoholic solvents. Utilizing previously crystallized ( )-4, the
greatest enantioenrichment (97.3% ee)10 was achieved by salt
formation in EtOH [SDA-3A, 190 proof (the SDA-3A
designation indicates denaturing with 5 parts methanol)], but
the recovery was modest (36%). This reduction in yield is
presumably due to water present in the ethanol leading to
increased solubility of the product salt (Figure 4). The use of
anhydrous solvents such as ethanol (200 proof) and n-BuOH
a
LCAP = liquid chromatography area percent.
of salt 26, and the addition of solid to the refluxing solution
caused excessive foaming. Due to the uncontrolled crystal-
lization, excess fumaric acid contaminated the isolated product.
Nonetheless, this procedure offered the first isolable, solid
intermediate in this sequence.
Modifications were necessary to make this salt formation
amenable to 20 L scale, as better control of both crystallization
rate and purity upgrade were required. The foaming observed
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Figure 4. Optimization of the (R)-O-acetyl mandelic acid resolution of
racemic 4.
was examined to circumvent this issue, and while both solvents
yielded comparable enantiomeric excess (93.8 and 93.5%,
respectively), the recovery with n-BuOH was superior (47 vs
42%). Further improvements with n-BuOH were realized by
seeding the crystallization (1% loading) and utilizing a
temperature cycle.16 This process allowed (−)-4 to be isolated
in 94.6% enantiomeric excess and 44% recovery from
previously isolated racemic 4.
With an optimal resolution developed using previously
crystallized ( )-4, we attempted to use the (R)-O-acetyl
mandelic acid crystallization as a means of both resolution and
purification. Upon completion of epoxide opening by BnNH2,
water was added to the reaction mixture and crude ( )-4 was
extracted into n-BuOH. This aqueous extraction was necessary
to remove lithium chloride (its presence leads to uncontrolled
precipitation of the racemate during the salt formation), and
upon addition of O-acetyl mandelic acid, 28 was produced in
43% yield and 96.0% ee (Scheme 5).10 The chemical purity of
(−)-4 that was isolated after salt break was greater than 99.9
LCAP, indicating that the crystallization effectively rejected the
impurities from the epoxide opening sequence.
The enantiomeric excess garnered from the resolution was
still insufficient for our purposes; however, the route to
coupling partner 2 offered three opportunities for enantioen-
richment. Initially we examined crystallization of the material
resulting from salt break of 28 (option 1, Figure 5). It was
found that either acceptable enantioenrichment or recovery
could be achieved by crystallization from varying ratios of
toluene/heptane, but both could not be realized simulta-
neously. The second option (Figure 5) involved conversion of
salt 28 to the coupling partner 2 and then crystallization from
toluene/heptane. Unfortunately, a similar outcome to the
crystallization of (−)-4 (either good recovery or chiral purity,
but not both) was found. The final option investigated (option
3, Figure 5) involved simple recrystallization of salt 28 resulting
from the resolution. Since we were now separating diastereo-
meric salts rather than enantiomers, this enantioenrichment
strategy proved to be the most effective. A range of alcoholic
solvents were surveyed, and recrystallization from ethanol
(SDA-3A 190 proof, 10 vol) yielded 28 in 99.9% ee with an
Figure 5. Strategies investigated for enantioenrichment.
acceptable 93% recovery.10 With an enantioenrichment strategy
in place, it appeared that we could efficiently execute the
sequence on 20 L scale. This material (28) could then be
converted to coupling partner 2 using the current chemistry or
be used to explore alternative protecting strategies for coupling.
However, at this point we obtained occupational toxicology
data that necessitated modification to our isolation strategy.
A local lymph node assay (LLNA) identified the epoxide
fumaric acid salt (26) as a dermal sensitizer.17 This introduced
material handling restrictions, and we sought to eliminate the
formation/isolation of the fumaric acid salt entirely. This would
stress our resolution crystallization, which would now afford the
only opportunity for purification from benzyl chloride/pyridine.
Progression through the sequence yielded epoxide 22, which
was not isolated, but instead carried directly into the epoxide
opening process. Reaction of crude 22 with BnNH2 behaved
similarly to when isolated epoxide salt 26 was used, and with
the dark brown stream of ( )-4 in hand (60 LCAP), we were
now ready to test the limits of our resolution in terms of
impurity purge. Using the previously developed conditions (n-
BuOH, 1% seeding, 1 temperature cycle), target salt 28 was
isolated as a white crystalline solid (29% yield from BnCl; 97
LCAP, 95.0% ee) on a 20 L scale. This material was then
recrystallized from ethanol (SDA-3A, 190 proof) for
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enantioenrichment and chemical purification (94% recovery,
100 LCAP, 99.8% ee) to produce 28 in 27% overall yield from
benzyl chloride (Scheme 6). More importantly, this outcome
demonstrated that formation/isolation of dermal sensitizer 26
is not necessary.
generation 20 L route required five steps and three
crystallizations to obtain O-acetyl mandelic salt 28 in 23%
overall yield (100 LCAP and 99.9% ee). At this point, epoxide
salt 26 was identified as a dermal sensitizer, and the process was
modified to eliminate formation/isolation of this compound.
This further streamlined the route to 28 and allowed us to
arrive at our current process. It was estimated that this route
would offer a cost reduction of 60% when compared to the
current strategy utilizing pyroglutamic acid [for the multikilo-
gram production of intermediate (−)-4]. This potential savings
is remarkable, when one considers that more than half of the
material is removed during the resolution. A full account
reporting the development work toward the preparation of
BMS-690514 (1) on scale will be forthcoming.
a
Scheme 6. Optimized Sequence to 28
EXPERIMENTAL SECTION
■
General. Reactions were performed under an atmosphere of
nitrogen unless otherwise noted. Reagents were used as
received unless otherwise noted. Reported yields are for
isolated materials or calculated solution yields and are corrected
for potency. NMR spectra were recorded on a Bruker DRX-500
instrument and are referenced to residual undeuterated solvent.
The following abbreviations are used to explain multiplicities:
br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. Infrared (IR) spectra were recorded on a Perkin-
Elmer 1600 series FT-IR spectrometer. High-resolution mass
spectra (HRMS) were recorded on a Thermo Orbi-trap
Discovery instrument. Reaction calorimetry was studied using
an Omnical Insight RT-10 isothermal reaction calorimeter.
Synthesis of Tetrahydropyridine 21. Caution: Com-
pound 21 was found to catalyze the exothermic decomposition
of sodium borohydride. As a result, sodium borohydride should
be added to a solution of the pyridinium salt, instead of adding
the pyridinium salt solution to a slurry of sodium borohydride.
For further discussion, see text.
EtOH (SDA-3A, anhydrous, 2 L) was charged to a 20 L glass
reactor equipped with a reflux condenser. Benzyl chloride (800
g, 6.32 mol, 1.0 equiv) and pyridine (533 g, 6.74 mol, 1.07
equiv) were charged into the reactor, and the heating jacket was
set to 85 °C. The reaction was refluxed until HPLC analysis
(210 nm) indicated that benzyl chloride had been consumed
[<0.2 RLCAP (relative liquid chromatography area percent),
typically 8−10 h]. Upon reaction completion, the jacket was set
to −10 °C and water (2 L) was added once the internal
temperature reached −5 °C. A freshly prepared solution of
sodium borohydride (288 g, 7.61 mol, 1.20 equiv) in 0.01 N
aqueous NaOH (4 L) was charged over 4 h at a rate to
maintain the internal temperature below 20 °C. Proper venting
of the vessel and control of reaction rate should be used to
maintain the hydrogen gas concentration below the lower
explosion limit of 4%. After complete addition of the sodium
borohydride solution, the chiller was set to 0 °C and the
reaction held for 30 min. Upon reaction completion (<1
RLCAP of pyridinium 23), water (8 L) was added, and the
aqueous layer was extracted with MTBE (2 × 4 L). The
combined organics were washed with 15% brine (2 L), and the
tetrahydropyridine 21 present in the crude stream was
quantified by HPLC (930 g, 5.37 mol, 85%).
a
FA = fumaric acid; OAMA = (R)-O-acetyl mandelic acid.
SUMMARY
■
A strategy toward (−)-4 based on regioselective epoxide
opening with BnNH2 was selected for further development.
The optimized sequence produced O-acetyl mandelic salt 28 in
27% (100 LCAP, 99.8% ee)10 overall yield from benzyl chloride
in five steps and two isolations (see Figure 6 for route metric
Figure 6. Route metric comparison.
comparison). This compares favorably with the original lab
scale route, which required five steps, a reduced pressure
distillation, and two crystallizations to obtain 28 in 21% yield
(100 LCAP, 93.8% ee). Calorimetry studies determined that
the product (21) from reduction of pyridinium salt 23 catalyzes
the exothermic decomposition of sodium borohydride. This
precluded the use of a reverse addition protocol, and further
analysis allowed us to develop a process that removed the
potential for an uncontrolled exotherm on scale. The first
Synthesis of Epoxide 22. To a 20 L glass reactor
containing the MTBE stream from above was added water (5.6
kg). The MTBE was removed by distillation under reduced
pressure until the internal temperature reached 47 °C at 180
Torr. The resulting emulsion was cooled to 20 °C, and
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trifluoroacetic acid (765 g, 6.71 mol, 1.25 equiv) was added
over a period of 10 min (slight exotherm 20−30.4 °C). The
reaction was stirred for 20 min to obtain a slightly hazy
solution, and then N-chlorosuccinimide (861 g, 6.45 mol, 1.20
equiv) was added in one portion. The reaction was heated to 70
°C and held at this temperature for 4 h. Upon reaction
completion (<2 RLCAP of tetrahydropyridine 21), the reactor
contents were cooled to 10 °C over 1 h. To this solution was
added aqueous sodium hydroxide (2.3 L of 10 M, 23.0 mol,
4.28 equiv) over 15 min (exotherm from 10 to 26 °C),
followed by heating to 45 °C for 4 h, then cooling to 20 °C.
The reactor contents were extracted with MTBE (2 × 3 L), and
the combined organics were washed with water (1 L) and 1:1
water/brine (1 L). Quantitation of the reaction stream
determined that 817 g (4.32 mol, 68% overall from benzyl
chloride) of epoxide was present in solution. This material was
telescoped directly to the next step.
Optional Crystallization of Epoxide 22 as the Fumaric
Acid Salt (26). Caution: Compound 26 was identified as a
dermal sensitizer. In order to perform this crystallization, 2-
MeTHF (2 × 2 L) should be substituted for MTBE in the
above extraction. Based on HPLC quantification, the crude 2-
MeTHF stream used in this example contained 1028 g (5.43
mol) of epoxide 22.
Acetone (4.95 kg), water (0.62 kg), and fumaric acid (624 g,
5.38 mol) were combined in a 20 L glass reactor; the slurry was
then heated to reflux and held for 1 h to dissolve the fumaric
acid. The solution was cooled to an internal temperature of 45
°C and stirred for 1 h. The fumaric acid solution was seeded
with 100 g of previously prepared epoxide salt 26, and the
reaction stream (epoxide solution in 2-MeTHF) was added at a
rate of 300 mL/min (total addition time, ∼15 min). The slurry
was cooled to −5 °C over 2 h, and then held for an additional
12 h at this temperature. The product was filtered, the cake
washed with acetone (2 × 1.5 L), and then dried in a vacuum
oven (45 °C). The epoxide salt 26 (962 g, 3.15 mol, 58% from
benzyl chloride) was obtained as a beige solid. mp = 161−163
°C; IR (film): vmax = 3412, 3029, 2589, 1712, 1654, 1526 cm−1;
1H NMR (DMSO-d6, 500 MHz): δ = 7.29 (m, 5 H), 6.61 (s, 2
H), 3.46 (d, J = 1.5 Hz, 2 H), 3.19 (m, 2 H), 2.96 (ddd, J =
13.5, 4.0, 1.5 Hz, 1 H), 2.55 (d, J = 13.5 Hz, 1 H), 2.31 (ddt, J =
11.5, 5.0, 1.5 Hz, 1 H), 2.13 (ddd, J = 6.0, 5.0, 2.5 Hz, 1 H),
1.91 (m, 2 H) ppm; 13C NMR (DMSO-d6, 125 MHz): δ =
166.6, 136.4, 134.3, 129.2, 128.3, 127.5, 60.7, 51.1, 49.9, 49.6,
45.2, 24.4 ppm; HRMS calcd for C12H15NOH+ [M + H+]
190.1232, found 190.1221.
If the fumaric acid salt of the epoxide 26 is formed, washing
with aqueous base is required prior to the epoxide opening
step. To a 20 L glass reactor was charged epoxide salt 26 (975
g, 3.19 mol, 1.0 equiv) and 2 N NaOH (3.69 kg, 7.09 mol, 2.22
equiv) to afford a slurry which was stirred for 10 min. MTBE
(4.31 kg) and brine (3.43 kg) were charged to the reactor, and
the contents were mixed for 10 min. The layers were allowed to
separate, and the aqueous layer was removed. The organic layer
was again washed with a combination of brine (0.75 L) and 2 N
NaOH (0.75 L). After removal of the aqueous layer, the MTBE
solution of the epoxide is used in the opening/crystallization
sequence as described below.
was then added at a rate to maintain a constant volume of 4.5 L.
Distillation was continued until the distillate contained less than
5% MTBE (1H NMR). The reactor contents were cooled to 20
°C (internal), and an additional 3.5 L of acetonitrile was added
to bring the total reactor volume to 8 L. Benzylamine (559 g,
5.22 mol, 1.2 equiv) and lithium chloride (184 g, 4.34 mol, 1.0
equiv) were added, and the reaction was stirred at 20 °C for 16
h and then heated to 50 °C for an additional 2 h (<1 RLCAP of
22). n-Butanol (8 L) was charged and the acetonitrile was
removed by reduced pressure distillation until the distillate
contained less than 5% acetonitrile (1H NMR), and then the
total volume was reduced to 8 L. The internal temperature was
reduced to 35 °C, and the organic layer was washed with water
(5 L, then 1.5 L). The water that remained in the organic layer
was removed by constant volume azeotropic distillation, until
the distillation reached a constant temperature of 56 °C at 44
Torr. n-Butanol was then added to bring the total volume to
10.5 L. The solution yield of ( )-4 was determined to be 90%
at this stage, and the charge of (R)-O-acetyl mandelic acid (29,
1.0 equiv based on 4) was adjusted accordingly. The
temperature was increased to 78 °C, and 29 (377 g, 1.94
mol, 0.50 equiv based on in-process 4) was added as a solution
in n-butanol (0.75 L). The temperature was reduced to 70 °C,
28 (9 g, 0.018 mol, 1 wt %) was added as seeds, and then 29
(377 g, 1.94 mol, 0.50 equiv based on in-process 4) was added
as a solution in n-butanol (0.75 L). The slurry was held at 70
°C for 20 min, cooled to 20 °C over 2 h, and held at this
temperature for 12 h. The slurry was then heated to 60 °C and
held for 1 h, after which the temperature was reduced to 20 °C
over 3 h and held for an additional 2 h. The solids were
collected by vacuum filtration, and the cake was washed with n-
butanol (4 × 1 L) until the washes became colorless. The solid
was dried for 48 h in a vacuum oven (50 °C, 25 Torr) to yield
28 (903 g, 1.84 mol, 95% ee, 29% overall yield from benzyl
chloride) as a white crystalline solid.
Optional Recrystallization of 28 for Upgrade of
Enantiomeric Excess. Salt 28 (725 g, 1.48 mol, 95% ee)
was charged to a 20 L glass reactor, followed by ethanol (SDA-
3A 190 proof, 5.8 kg). The slurry was stirred for 10 min and
then heated to reflux until a solution resulted. The solution was
cooled to 65 °C over 1 h, seeded with 28 (7.0 g, 99.9% ee), and
stirred at this temperature for 30 min. The slurry was cooled to
0 °C over 2 h and then held for an additional 30 min. The
product was collected by vacuum filtration, and the cake was
washed with isopropanol (3 × 1.2 L). The solids were dried in a
vacuum oven (45 °C) for 12 h to yield 28 (682 g, 94%
recovery, 99.8% ee) as a white crystalline solid. mp (DSC) (10
°C/min) = onset 171 °C, peak 173 °C; [α]D25 = −63.9 (c = 1.0,
MeOH); IR (film): vmax = 3123, 3024, 2972, 2438, 1730, 1637,
1
1583, 1374, 1250 cm−1; H NMR (CD3OD, 500 MHz): δ =
7.54−7.40 (m, 7 H), 7.35−7.25 (m, 8 H), 5.77 (s, 1 H), 4.25
(d, J = 13.5 Hz, 1 H), 4.22 (d, J = 13.5 Hz, 1 H), 3.75 (dt, J =
9.5, 4.5 Hz, 1 H), 3.63 (d, J = 13.0 Hz, 1 H), 3.56 (d, J = 13.0
Hz, 1 H), 3.08 (ddd, J = 11.0, 5.0, 2.0 Hz, 1 H), 2.96 (m, 1 H),
2.82 (m, 1 H), 2.13 (s, 3 H), 2.15−2.04 (m, 2 H), 1.95 (t, J =
10.0 Hz, 1 H), 1.68 (ddd, J = 13.5, 12.0, 4.5 Hz, 1 H) ppm; 13
C
NMR (CD3OD, 125 MHz): δ = 176.10, 172.58, 138.74, 138.19,
133.83, 130.92, 130.67, 130.42, 130.35, 129.61, 129.41, 129.25,
128.98, 128.85, 78.98, 69.16, 63.01, 61.80, 59.87, 52.27, 50.23,
27.38, 21.23 ppm; HRMS calcd for C19H24N2OH+ [M + H+]
297.1967, found 297.1956.
Epoxide Opening and Crystallization/Resolution To
Prepare 28. The solution of crude epoxide 22 (∼817 g, 4.32
mol, 1.0 equiv) in MTBE (6 L) was placed in a 20 L glass
reactor and then distilled under reduced pressure (60 °C, 100
Torr) to an approximate volume of 4.5 L. Acetonitrile (5.65 kg)
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dx.doi.org/10.1021/op300174w | Org. Process Res. Dev. 2012, 16, 1558−1565

Organic Process Research & Development
Article
(13) Brown, H. C.; Mead, E. J.; Subba Rao, B. C. J. Am. Chem. Soc.
1955, 77, 6209.
(14) (a) Martelli, P.; Caputo, R.; Remhof, A.; Mauron, P.;
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ian.young@bms.com.
Borgshulte, A.; Zuttel, A. J. Phys. Chem. C 2010, 114, 7173.
̈
(b) Shimizu, S.; Osato, H.; Imamura, Y.; Satou, Y. Org. Process Res.
Dev. 2010, 14, 1518.
Notes
The authors declare no competing financial interest.
(15) Use of the commercially available solution of NaBH4 in 14 N
NaOH led to numerous unidentified impurities and caused the
reaction mixture to turn dark in color.
(16) After the initial formation/crystallization of the salt, the 20 °C
slurry was reheated to 60 °C, held for 1 h, and then cooled to 20 °C
for isolation.
(17) Further testing is required to determine if the epoxide 22 itself is
responsible for this LLNA result, as it has been reported that fumaric
acid is not a skin sensitizer. Krieling, R.; Hollnagel, H. M.; Hareng, L.;
Digler, D.; Lee, M. S.; Griem, P.; Dreeßen, B.; Kleber, M; Albrecht, A.;
Garcia, C.; Wendel, A. Food Chem. Toxicol. 2008, 46, 1896.
ACKNOWLEDGMENTS
■
We would like to thank Drs. David Kronenthal, Rajendra
Deshpande, Robert Waltermire, Michael Cassidy, and Albert
Delmonte for careful review of this manuscript. Vic Rosso/
Mark Liu (high-throughput crystallization screens), Dr. Brent
Karcher/Merrill Davies (HPLC development), and Jonathan
Marshall (HRMS) are acknowledged for contributions to this
research.
DEDICATION
■
†This paper is dedicated to the memory of our friend and
colleague, Eric Sortore.
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(11) Throughout the Results section, the original (o) lab scale
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