Development of a Stereoselective Synthesis of (1 R,4 R)- and (1 S,4 S)-2-Oxa-5-azabicyclo[2.2.2]octane

Article abstract of DOI:10.1021/acs.oprd.1c00098

Despite the prevalence of morpholine derivatives and bridged heterocycles in medicinally relevant compounds, bridged bicyclic morpholines remain scarce because of the challenges associated with their synthesis. MRK A, an IDH1mut inhibitor for the treatment of glioma, derives its potency in part from substitution of a zigzag 2,5-bicyclic morpholine, 2-oxa-5-azabicyclo[2.2.2]octane, at C8. While existing entries suffered from low yields and lack of stereochemical control, we developed concise stereospecific routes toward both enantiomers of the zigzag morpholine antipode. The key common intermediate in the two routes was a chiral bicyclic lactone, which was readily synthesized following our previous synthesis of relebactam from optically pure (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (HPA). The desired (R,R) enantiomer for incorporation into MRK A required inversion of both stereocenters of the bicyclic lactone intermediate, which was accomplished by epimerization via a crystallization-induced diastereomer transformation process followed by a key Ti(OiPr)4-mediated intramolecular SN2 ring closure. By this method, the (R,R)-zigzag morpholine was synthesized in six steps from HPA in 25% overall yield.

Full text of DOI:10.1021/acs.oprd.1c00098

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Article
Development of a Stereoselective Synthesis of (1R,4R)- and
(1S,4S)‑2-Oxa-5-azabicyclo[2.2.2]octane
Matthew L. Maddess,* Ed Cleator,* Mariko Morimoto, Adrian Goodyear, Alejandro Dieguez-Vazquez,
Andrew Gibb, Andy Kirtley, Jie Wang, Ji Qi, Lingzhu Kong, Mahbub Alam, Stephen Keen,
Steven F. Oliver, Xin Wen, and Yu-Hong Lam
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ABSTRACT: Despite the prevalence of morpholine derivatives and bridged heterocycles in medicinally relevant compounds,
bridged bicyclic morpholines remain scarce because of the challenges associated with their synthesis. MRK A, an IDH1mut inhibitor
for the treatment of glioma, derives its potency in part from substitution of a zigzag 2,5-bicyclic morpholine, 2-oxa-5-
azabicyclo[2.2.2]octane, at C8. While existing entries suffered from low yields and lack of stereochemical control, we developed
concise stereospecific routes toward both enantiomers of the zigzag morpholine antipode. The key common intermediate in the two
routes was a chiral bicyclic lactone, which was readily synthesized following our previous synthesis of relebactam from optically pure
(2S,5S)-5-hydroxypiperidine-2-carboxylic acid (HPA). The desired (R,R) enantiomer for incorporation into MRK A required
inversion of both stereocenters of the bicyclic lactone intermediate, which was accomplished by epimerization via a crystallization-
induced diastereomer transformation process followed by a key Ti(OiPr)4-mediated intramolecular SN2 ring closure. By this method,
the (R,R)-zigzag morpholine was synthesized in six steps from HPA in 25% overall yield.
KEYWORDS: bicyclic morpholine, IDH1, crystallization induced diastereoselective transformation
INTRODUCTION
■
Morpholines and structurally related analogues have demon-
strated a wide range of biological activities and represent
privileged scaffolds in a number of medicinally relevant
compounds.1 The relatively low pKa of the nitrogen atom
(7.4 for N-methylmorpholine) coupled with the ability of the
oxygen atom to function as a weak hydrogen-bond acceptor
may allow the incorporation of morpholine to enhance the
solubility of a molecule without adversely affecting its
permeability under physiological conditions.2 Furthermore,
saturated ring systems provide rapid access to three-
dimensionality through substitution, which can be advanta-
geous from intellectional propery, pharmacokinetic, and
potency standpoints.3−5 Bridged analogues are of particular
interest, as they enable close conformational control over the
molecule without significantly impacting the lipophilicity.6
Figure 1. (A) Existing route to the synthesis of 2,5-bridged
bicyclomorpholine. (B) This work: stereoselective syntheses of the
two enantiomers from common intermediate 2.
A series of tricyclic diazepines were recently identified as
potential IDH1mut inhibitors for the treatment of glioma.7 A
promising target was MRK A, which features a “zigzag” 2,5-
bridged morpholine at C8. While scaffolds containing 3,5-
bridged morpholines have been previously synthesized and
bicyclomorpholine 1. Subsequently, concise stereoselective
routes to the two enantiomers 3 and 4 were successfully
studied, precedent for the 2,5-bridged isomer remains scarce.8
General accessibility of these pharmacophores was hampered
by the prohibitively high cost of commercially available
material as well as the existing synthetic entry, which consists
Special Issue: Excellence in Industrial Organic Syn-
thesis 2021
of eight steps and gives the racemic product 1 in <20% yield
(Figure 1A).9 Consequently, the 2,5-bridged isomer is found in
Received: March 21, 2021
only 0.02% of the literature, representing a largely unexplored
chemical space.10 Starting from readily accessible pyridine
derivatives, we first devised a racemic route to access
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A

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Scheme 1. First-Generation Route via Pyridine Reduction Entry
Scheme 2. Reaction Sequence to Access (S,S) Enantiomer 3
developed using key intermediate 2, which was inspired from
for intermediate 7 yielded the oxalic acid salt of 3 as a single
enantiomer. While analysis of the absolute configuration of 3
revealed that it was the opposite enantiomer of that required
for MRK A, the route offers concise and stereoselective access
to the (S,S) antipode for future applications.
Although a clear alternative to access 4 was to synthesize the
opposite enantiomer of 2, this required non-biocatalytic
entries, which were significantly less efficient and under-
developed. We thus sought to develop a synthetic route that
involved inversion of both stereocenters, where lactone 2 could
still serve as a key intermediate and a source of stereocontrol
(Scheme 3). We envisioned that an intramolecular SN2-type
our previous synthesis of relebactam (Figure 1B).11,12
RESULTS AND DISCUSSION
■
Initial quantities of 4 were synthesized starting from pyridine
derivative 5, as outlined in Scheme 1. Pt-catalyzed reduction of
5 yielded pipecolic acid 6 with an 86:14 cis:trans ratio,13,14
which was subsequently nosyl-protected and cyclized to yield
bicyclic lactone 7. Sodium borohydride reduction followed by
separation of the resulting enantiomers by supercritical fluid
chromatography (SFC) yielded diol 8, which was mono-
sulfonylated to form 9. Finally, an intramolecular nucleophilic
substitution under basic conditions yielded bicyclic morpho-
line 10, which was deprotected to afford the oxalic acid salt of
4 as a colorless solid. While this route provided sufficient
quantities of both enantiomers for initial studies, drawbacks
included high catalyst loadings and long reaction times for the
pyridine reduction as well as the SFC separation. While
asymmetric pyridine reduction has been reported,15,16 its
applications have been largely limited by its scope and
scalability.
Scheme 3. Retrosynthetic Analysis of 4 Starting from 4-Ns-
Protected 2
Given these synthetic challenges, we sought an alternative
route to access bicyclic lactone 7 in an enantioselective
manner. In a previous synthesis of relebactam (MK-7655),
(S,S)-bicyclic lactone 11 served as a key intermediate, and it
can be accessed on a multikilogram scale via a biocatalytic
pathway.11,12 We envisioned that leveraging this advanced
intermediate could provide a shorter stereoselective synthesis
of the desired bicyclic morpholine 4. At the time, long lead
times for bulk quantities of 2-nosyl chloride drove consid-
eration of the 4-nosyl derivative 2 as an alternative. Optically
pure (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (HPA)12
was protected and cyclized in a single step to yield lactone 2
(Scheme 2). Subjecting 2 to a reaction sequence similar to that
ring closure could occur from intermediate 16, which would
invert one of the stereocenters and form Ns-protected 4 (15)
as a single enantiomer. Primary alcohol 16 would be generated
from trans-methyl ester 17, which could be derived from base-
mediated epimerization of 18. The cis-methyl ester 18 was
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envisioned to be accessed via methanolysis of lactone 2
followed by tosylation of the free alcohol.
mitigated upon addition of methanol. Investigation of 1:1
mixtures of IPAc, acetonitrile, or toluene with methanol
revealed toluene:methanol to be the solvent system with the
cleanest profile and minimal decomposition. Since the reaction
was homogeneous under these conditions, excess methanol (to
attain 4:1 methanol:toluene) was later added as an antisolvent,
which resulted in a 69% isolated yield of 17 with 17% liquor
loss on a 5 g scale. Ultimately, running the reaction as a slurry
in 4:1 methanol:toluene and seeding with a small amount of 17
enabled us to reduce the liquor loss to 9%, and the desired
diastereomer was isolated in 79% yield upon scale-up (Scheme
4).
The ring opening of 2 was initially conducted with
potassium carbonate in methanol, which led to formation of
a 2:1 cis:trans mixture of the methyl ester product over time.
This undesired epimerization was eliminated by using 4-
dimethylaminopyridine (DMAP) instead of potassium carbo-
nate, and the crude cis-methyl ester was directly subjected to
tosylation conditions. Running this reaction sequence on scale
afforded 18 in 97% yield over two steps (see Scheme 5).
Density functional theory (DFT) calculations17 were
performed on trans-ester 17 and cis-ester 18 to estimate the
relative stabilities of the two diastereomers. An energy
difference of 1.3 kcal/mol in favor of 17 was calculated,
supporting the epimerization approach as a viable strategy.
Epimerization conditions were thus explored, starting with a
brief survey of bases (Table 1). Lithium hexamethyldisilazane
Scheme 4. Optimized CIDT Epimerization Conditions to
Obtain Trans Isomer 17
Table 1. Base Optimization for Epimerization of 18
entry
base (equiv)
conditions
THF, r.t.
1:1 THF:MeOH, r.t.
1:1 PhMe:MeOH, 55 °C
1:1 PhMe:MeOH, 55 °C
1:1 THF:MeOH, r.t.
result
1
2
3
4
5
LiHMDS (1.0)
K2CO3 (0.7)
TEA (1.0)
DIPEA (1.0)
DBU (1.0)
decomposition
55:45 trans:cis
trace epimerization
trace epimerization
3:1 trans:cis
We next investigated reaction conditions for the reduction of
methyl ester 17 to afford primary alcohol 16. Initial attempts
with sodium borohydride resulted in sluggish reactivity, even in
the presence of an additive such as NaOMe or CaCl2.19,20
While lithium borohydride demonstrated increased reactivity,
competitive reduction of the 4-nosyl group to the correspond-
ing hydroxylamine presented a significant challenge. This
undesired reactivity was highly solvent-dependent: THF
yielded the undesired hydroxylamine product as the major
product (Table 3, entry 1), whereas alcoholic solvents yielded
(LiHMDS) in tetrahydrofuran (THF) led to decomposition of
the starting material (entry 1), whereas K2CO3 generated an
∼1:1 mixture of trans and cis isomers despite solubility issues
(entry 2). Triethylamine (TEA) and diisopropylethylamine
(DIPEA) resulted in little reactivity, even upon heating to 55
°C (entries 3 and 4). Fortunately, 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) enabled epimerization to occur, affording
a 3:1 trans:cis ratio in a THF:MeOH solvent mixture (entry
5).
Table 3. Solvent Screen for Selective Ester Reduction to
Obtain Primary Alcohol 16
Upon identification of a suitable base, we envisioned a
crystallization-induced diastereomer transformation (CIDT)
process, where dynamic crystallization would enable efficient
product recovery while shifting the equilibrium further toward
the desired diastereomer.18 We screened solvent conditions to
determine appropriate crystallization conditions and found that
the desired product 17 was less soluble than 18 in isopropyl
acetate (IPAc), acetonitrile, and toluene (Table 2, entries 5, 7,
and 10).
Running the reaction with 3 volumes of IPAc or toluene
resulted in a large amount of decomposition, which was
entry
solvent
SM (%)
16 (%)
impurity (%)
1
2
3
4
5
6
7
8
THF
0
86
0.4
19
47
12
0.7
0
8
13
84
57
48
88
98
91
70
1.2
10
10
0.2
0
MeOH
EtOH
Table 2. Solubilities of Cis and Trans Diastereomers
IPA
solubility(mg/mL)
THF:MeOH (1:1)
THF:MeOH (3:1)
THF:MeOH (9:1)
THF:EtOH (9:1)
entry
solvent
cis
2.8
1.1
trans
0
1.4
1
2
3
MeOH
EtOH
IPA
4.5
2
<1
<1
4
5
6
7
8
9
10
EtOAc
IPAc
THF
MeCN
water
heptane
toluene
>96.5
37.2
>102
>100
<1
81.7
26.8
>98
>86
<1
16, albeit at lower overall conversions (entries 2−4). Improved
conversions and selectivity were observed under mixed-solvent
conditions, with 9:1 THF:methanol yielding the optimal
results (entry 7).
In preparation for running the reduction on scale, potential
risks involving offgassing and thermal runaway due to the
exothermicity of the reaction were first evaluated. Upon
<1
27.9
<1
17.3
C
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Figure 2. (A) RC-1 calorimetry data under unoptimized small-scale conditions, where LiBH4 was added over 30 min at 10 °C in THF:MeOH
(9:1). (B) RC-1 calorimetry data under the optimized conditions, where LiBH4 was added over 3 h at 10 °C in the presence of 20 volumes of IPAc.
(C) Optimized conditions for reduction reactions run on scale.
addition of lithium borohydride over 30 min at 10 °C,
calorimetric data obtained using an RC-1 reaction calorimeter
from Mettler Toledo21 indeed indicated large and uncontrolled
gas release, associated with the decomposition of excess
borohydride after reaction completion (Figure 2A).
Table 4. Conditions Screened to Enable SN2 Ring Closure
Furthermore, this was accompanied by a significant
secondary exotherm. Analysis using the Advanced Reactive
System Screening Tool (ARSST)22 was undertaken to define
the optimal reaction conditions for a safe process. IPAc was
identified as a sacrificial solvent that could function as a
thermal heat sink for the reaction, but with a significantly lower
rate of reduction relative to the methyl ester substrate 17.
Additionally, ARSST analysis (with a 2 K/min ramp) revealed
that the thermal profile of the reaction was highly dependent
upon the rate of addition of the reductant. Addition times
under 30 min all resulted in self-heating of the reaction (ΔTadd
≈ 80K), which was exacerbated at elevated temperatures.
Increasing the addition time to 3 h as well as increasing the
amount of IPAc from 10 to 20 volumes proved to be critical in
controlling the maximum heat flow of the reaction. The
optimized reaction conditions are shown in Figure 2C. Under
these conditions, gas release first occurs over the initial period
of borohydride addition, which is followed by a slow and
controlled background gas release until full consumption of
excess borohydride (Figure 2B). The reduction was success-
fully conducted on methyl ester 17 to afford an 80% yield of
the desired alcohol product 16.
entry
conditions
additive
yield of 15 (%)
1
2
3
4
5
NMP, 100 °C, 72 h
2-butanol, 100 °C, 168 h
2-butanol, 100 °C, 72 h
NMP, 80 °C, 72 h
−
−
45
56
52
46
91
DIPEA
Sc(OTf)3
Ti(OiPr)4
DMF, 80 °C, 16 h
were later identified as regioisomeric elimination products as
well as the hemiaminal resulting from the enamine. Switching
the solvent to 2-butanol resulted in only marginal improve-
ments in the yield, despite long reactions times and elevated
temperatures (entry 2), and addition of DIPEA as a base
additive also did not increase the yield (entry 3). Though
relatively uncommon, Lewis acids such as AlCl3 and Zn(OTf)2
have been shown to facilitate ether formation through
nucleophilic substitution by primary alcohols, likely via
generation of a nucleophilic metal alkoxide or by activation
of the electrophile.23,24 We wondered whether a similar
approach could be undertaken and screened a variety of
metal Lewis acid additives under polar aprotic solvent
One of the final key steps in our synthetic route toward 4
was the ring closure of 16 to form the morpholine scaffold.
Initially, we tested heating conditions with N-methylpyrroli-
done (NMP) (Table 4, entry 1), which gave modest yields of
15 in addition to a mixture of impurities. These impurities
D
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Scheme 5. Optimized Synthetic Route to Access Bicyclic Morpholine 4
conditions. While AlCl3, AgOTf, FeCl3, BF3·THF, In(OTf)3,
and La(OTf)3 all gave poor conversions and selectivities for
the desired product, Sc(OTf)3 in NMP at 80 °C gave a
significantly better yield and 15:impurity ratio (85:15) (entry
4). While this was promising, there were several challenges: the
reaction stalled even with 3 equiv of Sc(OTf)3, and the high
cost of the reagent could hinder scale-up efforts. Gratifyingly,
we discovered that Ti(OiPr)4 (1 equiv) served as an excellent
alternative, where full conversion and a 91% assay yield were
observed after just 16 h. Furthermore, direct isolation of the
product was enabled by simple addition of water to afford 15
in 83% isolated yield after filtration and drying with a low
residual titanium concentration (116 ppm).
Deprotection of 15 was initially conducted with dodeca-
nethiol (DDT) and Cs2CO3 in MeOH, which gave complete
conversion after 30 min at 50 °C. Attempts at product isolation
were problematic because of the solubility of Cs+ in MeOH,
resulting in a low-potency isolated solid. While switching to
K2CO3 in a 10:1 MeCN:MeOH mixture appeared to improve
the product recovery, the results were largely inconsistent upon
scale-up of the reaction. Analysis of the reaction mixture by 1H
NMR spectroscopy revealed the presence of carbamic acid, an
indication that CO2 generated from the carbonate base
interacted with the free amine. Fortunately, this issue was
overcome by employing NaOH as an alternative base. While in
earlier iterations 4 was isolated as the oxalic acid salt, we
discovered that the benzoate salt exhibited greatly improved
solubility in organic solvents for subsequent reactions.
Deprotection of 15 proceeded in 73% yield and afforded
product 4 in six steps from HPA in an overall yield of 25%
(37% from intermediate 2) (Scheme 5).
phores and encourage their incorporation into other
medicinally relevant compounds.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise noted, all of
the experiments described herein were carried out under a
nitrogen atmosphere. All of the reagents and solvents were
commercially available and used without further purification
unless indicated otherwise. HPA (>99.5% ee, Chemical Purity
>98%) was procured from API Corporation (Fukuoka, Japan).
Yields reported are for isolated, spectroscopically pure
compounds. NMR spectra were recorded on a Bruker 300,
400, or 500 MHz instrument. The residual solvent protons
(1H) or the solvent carbons (13C) were used as internal
1
standards. H NMR data are presented as follows: chemical
shift in parts per million downfield from tetramethylsilane
(multiplicity, coupling constant, integration). The following
abbreviations are used in reporting NMR data: s, singlet; br s,
broad singlet; d, doublet; t, triplet; q, quartet; qt, quartet of
triplets; dd, doublet of doublets; dt, doublet of triplets; AB, AB
quartet; m, multiplet. High-resolution mass spectrometry was
performed on a Waters Xevo G2-XS Qtof spectrometer. SFC
data were tested by Waters UPCC, Shimadzu SFC-MS 2020,
and Shimadzu LC-20AT-UV instruments. Optical rotation was
measured using a Rudolph Research Analytical Autopol III
automatic polarmeter, and melting points were measured with
a Tianjin Analysis Instrument Factory RY-2 melting point
apparatus. (See the Supporting Information for more details on
the respective spectra).
Preparation of (1S,4S)-5-(4-Nitrophenylsulfonyl)-2-oxa-5-
aza-bicyclo[2.2.2]octan-3-one (2). To a stirred solution of
HPA (9.90 kg, >99.5% ee, >98% wt %) in acetonitrile (54.5
kg) was added triethylamine (13.8 kg) at 20 °C. The solution
was stirred at the same temperature for 10 min before addition
of a premade solution of 4-nitrobenzenesulfonyl chloride (15.0
kg) in acetonitrile (19.5 kg) over 2 h at 20 °C. The resulting
mixture was stirred at 20 °C for a further 30 min after the
addition. Triethylamine (13.8 kg) was charged, and after 10
min of stirring, a premade solution of 4-nitrobenzenesulfonyl
chloride (15.0 kg) in acetonitrile (19.5 kg) was again added
over 2 h at 20 °C. The reaction mixture was then stirred at the
same temperature for 2 h after the addition. To quench the
reaction, water (119 kg) was added to the reaction mixture
over 1 h, and the resulting slurry was cooled to 0 °C and aged
for 30 min. The mixture was filtered and washed with a cooled
(<5 °C) solution of acetonitrile (19.7 kg)/water (25 kg) and
again with water (50 kg). The solids were dried under vacuum
CONCLUSIONS
■
We have developed efficient and stereoselective routes toward
3 and 4, the two enantiomers of the zigzag 2,5-bridged
morpholine antipode. The two routes leverage chiral bicyclic
lactone 2 as a common intermediate, which was readily
synthesized following a previously developed route toward
relebactam. In order to obtain the desired enantiomer 4 for
incorporation into MRK A, inversion of both stereocenters in
the molecule was necessary, and this was accomplished by
epimerization via CIDT followed by a key intramolecular
Ti(OiPr)4-mediated SN2 ring closure. Finally, zigzag morpho-
line 4 was utilized in the total synthesis of MRK A, an
IDH1MUT inhibitor, which will be elaborated in future
communications. The developed routes provide greatly
enhanced access to these relatively unexplored pharmaco-
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1
at about 40 °C to afford compound 2 in 67% yield. H NMR
(300 MHz, CDCl3) δ 8.41−8.44 (m, 2H), 8.11−8.08 (m, 2H),
4.89 (m, 1H), 4.39 (d, J = 2.3 Hz, 1H), 3.62 (m, 1H), 3.42 (m,
1H), 2.18−2.14 (m, 1H), 2.00−1.83 (m, 3H); 13C NMR (75
MHz, CDCl3) δ 168.58, 150.74, 142.32, 129.64, 125.20, 73.94,
51.97, 48.28, 24.81, 22.75; HRMS (ESI) m/z [M + H]+ calcd
for C12H13N2O6S+ 313.0494, found 313.0489; mp 97−99 °C;
>99% ee; [α]1D9 −7.2 (c 1.03, DCM).
M, 22.3 kg) was charged, initially in small, 1/10th portions of
the reagent, while the gas evolution and temperature profile
were monitored to ensure a controlled addition. The reaction
temperature was maintained below 12 °C at all times
throughout the addition. After the addition was complete,
the reaction mixture was stirred for 12 h at 10 °C, after which
the reaction was quenched by portionwise addition of 10%
aqueous citric acid solution (11.6 kg in 104.2 kg of deionized
(DI) water) over 1 h at 5 °C. The organic layer was separated,
and THF (77.2 L) was added. The mixture was washed with
5% aqueous NaHCO3 (5.8 kg in 110 kg of DI water) and 10%
brine solution (9.7 kg in 86.8 kg of DI water). Upon
concentration of the organics to a volume of 155 L, the
solution was warmed to 50 °C and charged with 16 seed (27
g) and toluene (200 L). The solution was then concentrated to
155 L, cooled to 20 °C, and filtered. The solids were washed
with 2-propanol (57 L) and dried in vacuo at 50 °C under a
sweep of N2 for 12 h to afford compound 16 in 80% yield. 1H
NMR (300 MHz, DMSO-d6) δ 8.45−8.34 (m, 2H), 8.04−7.94
(m, 2H), 7.82−7.73 (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 4.85 (t,
J = 5.6 Hz, 1H), 3.92 (m, 2H), 3.68 (m, 1H), 3.57−3.35 (m,
2H), 3.11 (m, 1H), 2.44 (s, 3H), 1.83−1.72 (m, 1H), 1.72−
1.54 (m, 2H), 1.44−1.26 (m, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 150.21, 146.28, 145.76, 133.19, 130.76, 128.64,
127.96, 125.27, 75.70, 59.24, 53.60, 44.12, 25.60, 23.48, 21.58,
Preparation of Methyl (2S,5S)-1-((4-Nitrophenyl)sulfonyl)-
5-(tosyloxy)piperidine-2-carboxylate (18). To a mixture of 4-
nosyl HPA lactone 2 and 4-dimethylaminopyridine (12.28 kg)
was added methanol (157 L), and the solution was stirred for
12 h at 20 °C. Most of the solvent (157 L) was removed by
distillation, and acetonitrile (157 L) was added before the
reaction mixture was subjected to further distillation to remove
residual MeOH (60 L). To this solution was added tosyl
chloride (17.25 kg), and the reaction mixture was cooled to 0
°C. Triethylamine (10.76 kg) was added while the temperature
was maintained below 10 °C. The reaction mixture was aged
for 1 h at 0 °C, warmed to 20 °C, and stirred overnight. Water
(78.5 kg, 4.5 vol) was added to the reaction mixture over 15
min, after which the mixture was aged for another 15 min.
After the formation of a generous seed bed, additional water
(157 kg, 9 vol) was added over 30 min, followed by a 15 min
age. The mixture was filtered and washed with 3:2 water/
acetonitrile (45 kg of water, 23.58 kg of acetonitrile). The
solids were dried at 50 °C under a sweep of N2 for 12 h to
+
0.56; HRMS (ESI) m/z [M + H]+ calcd for C19H23N2O8S2
471.0896, found 471.0893; mp 78−80 °C; >99% ee; [α]D19
−2.2 (c 0.99, DCM).
1
afford compound 18 in 97% yield. H NMR (400 MHz,
DMSO-d6) δ 8.45−8.37 (m, 2H), 8.03−7.95 (m, 2H), 7.84−
7.77 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 4.78−4.72 (m, 1H),
4.24 (m, 1H), 3.77 (m, 1H), 3.51 (s, 3H), 3.01 (m, 1H), 2.44
(s, 3H), 2.15−2.05 (m, 1H), 1.83−1.68 (m, 2H), 1.44−1.30
(m, 1H); 13C NMR (101 MHz, DMSO-d6) δ 169.95, 150.39,
145.81, 144.77, 133.22, 130.77, 128.90, 127.99, 125.10, 75.08,
54.32, 52.89, 45.67, 26.94, 25.74, 21.58, 1.61; HRMS (ESI) m/
Preparation of (1S,4R)-5-((4-Nitrophenyl)sulfonyl)-2-oxa-
5-azabicyclo[2.2.2]octane (15). To alcohol 16 (15.4 kg) was
added DMF (80 kg), and the solution was stirred until it was
homogeneous. Ti(OiPr)4 (8.7 kg) was added, together with
additional DMF (1 kg). The reaction mixture was heated to 80
°C, stirred for 17 h, and then cooled to 20 °C. Water (14 kg)
was charged over a period of 30−60 min, after which the
mixture was aged for 1 h to form a good seed bed. Water (70
kg) was again charged over a period of 1−2 h, and the mixture
was again aged for 2 h. The mixture was filtered and washed
with DMF:water (11.5 kg of DMF, 24 kg of water) and again
with water (36 kg). The solids were dried in vacuo at 50 °C
under a sweep of N2 overnight to afford compound 15 in 83%
+
z [M + H]+ calcd for C20H23N2O9S2 499.0845, found
499.0840; mp 89−92 °C; >99% ee; [α]1D9 5.8 (c 1.02, DCM).
Preparation of Methyl (2R,5S)-1-((4-Nitrophenyl)sulfonyl)-
5-(tosyloxy)piperidine-2-carboxylate (17). To a solution of
cis-ester 18 (24 kg) in 1:4 methanol:toluene (151.7 kg of
MeOH, 41.8 kg of toluene) was added DBU (7.33 kg) and
trans-ester 17 seed (50 g) at 20 °C. After 52 h at the same
temperature, the cis:trans ratio of the liquors was 28.6:71.4,
and the reaction mixture was cooled to −5 °C. After 30 min,
the slurry was filtered and washed with cooled (15 °C)
methanol (75 kg). The solids were dried at 45 °C in vacuo
1
yield. H NMR (400 MHz, CDCl3) δ 8.44−8.36 (m, 2H),
8.09−7.99 (m, 2H), 3.99 (m, 2H), 3.88−3.76 (m, 2H), 3.71
(m, 1H), 3.54 (m, 1H), 2.22−2.00 (m, 2H), 1.88 (m, 1H),
1.76−1.64 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 150.12,
145.32, 128.20, 124.51, 69.63, 65.26, 50.85, 47.81, 25.79,
25.23; HRMS (ESI) m/z [M + H]+ calcd for C12H15N2O5S+
299.0702, found 299.0790; mp 88−90 °C; >99% ee; [α]D19
+4.3 (c 0.82, DCM).
1
under a sweep of N2 to afford compound 17 in 79% yield. H
NMR (400 MHz, DMSO-d6) δ 8.35−8.27 (m, 2H), 8.06−7.98
(m, 2H), 7.71−7.63 (m, 2H), 7.48−7.42 (m, 2H), 4.94−4.87
(m, 1H), 4.72 (t, J = 2.8 Hz, 1H), 3.72 (d, J = 14.9 Hz, 1H),
3.40 (m, 1H), 3.33 (s, 1H), 2.43 (s, 3H), 2.02−1.79 (m, 2H),
1.67 (d, J = 14.9 Hz, 1H), 1.50 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ 175.30, 154.82, 150.26, 150.21, 138.16, 135.35,
133.59, 132.52, 129.59, 78.87, 59.53, 57.65, 51.24, 29.35,
26.31, 26.01; HRMS (ESI) m/z [M + H]+ calcd for
Preparation of (1S,4R)-2-Oxa-5-azabicyclo[2.2.2]octane
Benzoate (4). To a solution of dodecanethiol (34.4 g, 40.8
mL) in acetonitrile (270 mL) and MeOH (27 mL) at 10 °C
was added 10 M sodium hydroxide (14.9 mL) at 10 °C. The
resulting slurry was aged for 15 min before 4-nosyl zigzag
morpholine 15 (27 g) was charged. The reaction mixture was
heated to 50 °C, stirred for 1.5 h (reaction completion was
confirmed by an analytical assay), cooled to 20 °C, filtered
through a pad of solka-floc (27 g), and washed with MeCN
(270 mL) (an analytical assay confirmed that little product
remained on the solka-floc pad). Assay yields pre- and
postfiltration through solka-floc should be compared to ensure
that the desired product has been completely washed off the solid
support. Benzoic acid (10.7 g) was added to the filtrate, and the
+
C20H23N2O9S2 499.0845, found 499.0850; mp 90−92 °C;
>99% ee; [α]1D9.5 6.0 (c 0.85, DCM).
Preparation of (3S,6R)-6-(Hydroxymethyl)-1-((4-
nitrophenyl)sulfonyl)piperidin-3-yl 4-Methylbenzenesulfo-
nate (16). To trans-ester 17 (19.1 kg) were added IPAc
(382 L) and methanol (7.0 L), and the solution was cooled to
8 °C. Toluene (150 L) was charged, and the solution was
further cooled to −20 °C. Lithium borohydride in THF (3.75
F
https://doi.org/10.1021/acs.oprd.1c00098
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
mixture was stirred until the acid dissolved. The resultant
stream was transferred to a separatory funnel and washed with
heptane (3 × 200 mL), and the heptane layers were put aside
(no product was detected by an analytical assay). The
remaining solution (210 mL) was concentrated to approx-
imately 54 mL (∼2.5 vol relative to 100% theoretical product),
during which time self-seeding was observed. The suspension
was warmed to 40 °C, and MTBE (160 mL, 8 vol relative to
100% theoretical product) was added over 30 min. The slurry
was cooled to room temperature and aged overnight. The solid
was filtered, and the cake was washed with MTBE. The solids
were dried at 50 °C under a sweep of N2 for 12 h to afford 15.8
g of compound 4 as the benzoate salt in 73% yield (corrected
Lingzhu Kong − Pharmaron Beijing, Co. Ltd., Beijing 100176,
China
Mahbub Alam − Process Research and Development, Merck
Sharp & Dohme Ltd, Hoddesdon, Hertfordshire EN11 9BU,
U.K.
Stephen Keen − Process Research and Development, Merck
Sharp & Dohme Ltd, Hoddesdon, Hertfordshire EN11 9BU,
U.K.
Steven F. Oliver − Process Research and Development, Merck
Sharp & Dohme Ltd, Hoddesdon, Hertfordshire EN11 9BU,
U.K.
Xin Wen − Process Research and Development, Merck & Co.,
Inc., Boston, Massachusetts 02115, United States
Yu-Hong Lam − Computational and Structural Chemistry,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States; orcid.org/0000-0002-4946-1487
1
for 92 wt %). H NMR (400 MHz, DMSO-d6) δ 7.99−7.92
(m, 2H), 7.47−7.28 (m, 3H), 4.07 (m, 1H), 3.86−3.56 (m,
2H), 3.47−3.09 (m, 2H), 2.96−2.72 (m, 1H), 2.12−1.53 (m,
3H); 13C NMR (75 MHz, DMSO-d6) δ 170.37, 137.31,
130.66, 129.56, 128.09, 66.82, 62.94, 45.89, 43.81, 25.18,
22.32; mp 88−90 °C; >99% ee; [α]1D9 7.2 (c 0.4, acetonitrile).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.1c00098
Author Contributions
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00098.
■
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
sı
Notes
Experimental details, characterization data, relevant
computational data, NMR spectra and relevant super-
critical fluid chromatography traces (PDF)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank LC Campeau for support of this work and
helpful suggestions on the final manuscript.
AUTHOR INFORMATION
Corresponding Authors
Matthew L. Maddess − Process Research and Development,
Merck & Co., Inc., Boston, Massachusetts 02115, United
States; orcid.org/0000-0002-7273-528X;
■
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Authors
Mariko Morimoto − Process Research and Development,
Merck & Co., Inc., Boston, Massachusetts 02115, United
States
Adrian Goodyear − Process Research and Development, Merck
Sharp & Dohme Ltd, Hoddesdon, Hertfordshire EN11 9BU,
U.K.
Alejandro Dieguez-Vazquez − Process Research and
Development, Merck Sharp & Dohme Ltd, Hoddesdon,
Hertfordshire EN11 9BU, U.K.
Andrew Gibb − Process Research and Development, Merck
Sharp & Dohme Ltd, Hoddesdon, Hertfordshire EN11 9BU,
U.K.
Andy Kirtley − Process Research and Development, Merck
Sharp & Dohme Ltd, Hoddesdon, Hertfordshire EN11 9BU,
U.K.
Jie Wang − Pharmaron Beijing, Co. Ltd., Beijing 100176,
China
Ji Qi − Process Research and Development, Merck & Co., Inc.,
Rahway, New Jersey 07065, United States; orcid.org/
0000-0003-4585-6534
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