Convergent kilogram-scale synthesis of dual orexin receptor antagonist

Article abstract of DOI:10.1021/op3002678

MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.

Full text of DOI:10.1021/op3002678

Article
pubs.acs.org/OPRD
Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor
Antagonist
Melina Girardin,† Stephane G. Ouellet,† Danny Gauvreau,† Jeffrey C. Moore,‡ Greg Hughes,†,‡
́
́
Paul N. Devine,‡ Paul D. O’Shea,†,‡ and Louis-Charles Campeau*,†,‡
†Global Process Chemistry, Merck Frosst Center for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Queb
H9H 3L1
́
ec, Canada
‡Global Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its
first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a
three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome
by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O-alkylation with 5-fluoro-2-
hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.
The ketodiester 5 was screened against a variety of
commercially available transaminases. It was observed that the
dimethyl malonate-derived 5 was preferred to the larger diethyl
malonate substrate. The Vibrio transaminase12 provided the S-
enantiomer (undesired), whereas the majority of the
Cambrex13 enzymes and ATA-11714 were highly R-selective
(desired).15 Both isopropylamine and D-alanine were screened
with the R-selective enzymes as amine donors. In these initial
screening experiments, only reactions using ATA-117/D-alanine
reached complete conversion while affording >99% ee, and it
was selected for further development.
The biocatalytic transamination is described in Scheme 1.
Ketone substrate 5 was treated with a combination of three
enzymes to achieve full conversion to the R-amine.14 This first
enzyme and the pyridoxal-5′-phosphate cofactor enabled the
transfer of the amine from D-alanine to the ketodiester 5. The
intermediate aminodiester 6 spontaneously cyclized to the
desired piperidone 4, thus driving the equilibrium and avoiding
product inhibition of the transaminase. Catalytic turnover was
INTRODUCTION
■
The orexins (also named hypocretins) are hypothalamic
peptides independently identified by two research teams in
1998.1 Orexins operate as neurotransmitters in the central
nervous system and are involved in numerous physiological
systems, most notably, sleep regulation.2 The relation between
reduced orexin levels and narcolepsy has been demonstrated in
rodents, dogs, and humans.3 These findings suggested the
potential for an orexin receptor antagonist in the treatment of
sleep disorders. Suvorexant, a dual orexin receptor antagonist, is
currently in phase III clinical trials for the treatment of primary
insomnia.4 Our discovery efforts identified an additional dual
orexin receptor antagonist development candidate MK-6096
(1) based on an α-methylpiperidine carboxamide.5
RESULTS AND DISCUSSION
■
To support preclinical and clinical development, we required a
practical synthesis of 1 suitable for kilogram scale.6 Our
retrosynthetic plan for kilogram-scale deliveries is outlined in
Figure 1. Late-stage amide bond formation would allow for a
convergent synthesis from the chiral piperidine fragment 3 and
the acid 2. With this plan in place, the key synthetic challenge
that emerged was the enantioselective preparation of the α-
methylpiperidine core.7 To achieve this goal, we envisioned the
enantioselective reductive amination of ketone 5 which, upon
formation of the primary amine, could cyclize to afford
piperidone 4 setting the α-methyl stereocenter.8 This would
leave the methyl ester as a handle for installation of the side
chain. Ketone 5 would be obtained from the Michael addition
of readily available methyl vinyl ketone and dimethyl malonate
which are inexpensive and available on multikilogram scale.
Initial reductive aminations of 5 with ammonium formate
and Pd/C afforded lactam 4 in a yield of ∼70% providing proof
of concept for the proposed route.9 Considering strategies for
an asymmetric variant we selected enantioselective biocatalytic
transamination as an alternative to reductive amination.10,11
̂
further ensured via Le Chatelier principle by the reduction of
the pyruvate byproduct to lactate using lactate dehydrogenase
(LDH) and NADH as a hydride source. A third enzyme,
glucose dehydrogenase (GDH), was used to recycle NADH.
The reaction was performed in water with NaH2PO4;
continuous addition of 5 N NaOH was necessary to maintain
a pH of 7.4, which was found to be optimal. Loading studies
determined that the reaction could be successfully conducted in
a concentration range of 50−75 g/L of compound 5. Higher
concentration required an increase in the transaminase loading.
The reaction performed best when D-alanine was near its
solubility limit and glucose levels could be limited to 1.1−1.3
equiv.
The synthesis for the chiral piperidine alcohol fragment 8 is
presented in Scheme 2. Michael addition of dimethyl malonate
Received: September 23, 2012
© XXXX American Chemical Society
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Figure 1. Retrosynthesis of 1.
Scheme 1. Biocatalyzed transamination to piperidone 4
Scheme 2. Synthesis of chiral piperidine 8
to methyl vinyl ketone provided the transamination substrate 5.
Both the lactam and the ester carbonyls of the transamination
product 4 needed to be reduced to afford the piperidine 8. We
envisioned a chemoselective lactam reduction to take advantage
of the epimerization of a piperidine ester previously described.5
However, attempts with a variety of reducing agents were
unsuccessful. The concomitant reduction of both carbonyls
with LiAlH4 was also briefly explored but afforded incomplete
conversion even under forcing conditions. Given these results
and our short timeline for delivery, we opted for a two-step
reduction starting with the ester. In situ generated Ca(BH4)2 in
EtOH afforded a clean reduction to the primary alcohol 7.
Careful choice of solvent and control over reaction temperature
were required to avoid the onset of a significant exotherm.16
The diastereomeric ratio of 7 was 1.7:1 following the ester
reduction. The lactam could then be cleanly reduced using
lithium aluminium hydride solution in THF at 50 °C. The
volume-efficient Fieser workup allowed a good recovery of the
highly water-soluble piperidine product 8.17 Fortunately, the
diastereomeric purity could be greatly improved after this
second reduction, by forming the D-(+)-camphorsulfonic acid
salt 8·CSA (>40:1).
We next turned our attention to the development of a robust
O-selective alkylation of pyridone 13 to complete piperidine
fragment 3. In support of their SAR work, the medicinal
chemistry team had used a Mitsunobu reaction,18 which used
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Table 1. Effects of reagents in the optimization of SN2 reaction
entry
substrate
X =
solvent
base
10:11
1
2
3
4
5
6
9a
9b
9c
9d
9d
9d
Br
DMF
DMF
DMF
DMF
NMP
NMP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU
4.4:1
3.8:1
3:1
I
OMs
OTs
OTs
OTs
5.6:1
3.8:1
6.8:1
Cs2CO3
Table 2. Effects of Conditions in the Optimization of SN2 Reaction
a
a
entry
R =
temperature (°C)
concentration (M)
10:11
conversion (%)
1
2
3
4
5
6
7
CBz
CBz
CBz
CBz
CBz
CBz
Boc
35
50
65
50
50
60
60
0.2
0.2
0.2
0.1
0.05
0.1
7.2:1
6.8:1
5.3:1
7.5:1
8.6:1
7.2:1
10.6:1
82
97
>99
99
98
b
99
c
0.1
>99
a
b
c
Determined by HPLC analysis. 15g scale, 73% isolated yield (10:11 = 12:1). 45 g scale, 80% isolated yield (10:11 = 15:1).
Scheme 3. Preparation of piperidine 3
polymer-supported triphenylphosphine.5 The Mitsunobu re-
action had originally been selected for its high O- vs N-
chemoselectivity (typically >7:1). We decided to investigate the
possibility of using an SN2 reaction.19 Having gram quantities of
Cbz-protected piperidine 8 in hand from previous campaigns,20
we undertook substantial experimentation on a variety of
activated species (9a−d). Results revealed that judicious
choices of leaving group, solvent, and base were critical to
the success of the displacement (Table 1).
The tosylate leaving group was selected along with Cs2CO3
and NMP for further study of the nature of the nitrogen
protecting group, which could still be changed, in addition to
various reaction parameters. The effect of four reaction
parameters on conversion and chemoselectivity was studied:
base and pyridone 13 stoichiometries, temperature, concen-
tration. The last two variables turned out to have the most
impact on the reaction and were further studied to select
conditions for scale-up and evaluate the reaction robustness.21
Representative results from these experiments are presented in
Table 2. They revealed that higher dilution and lower
temperatures increased O-selectivity (entries 3−5). However,
conversion significantly improved at higher temperature
(entries 1−3).
We also studied the effect of replacing the CBz protecting
group by a Boc for ease of removal (entries 6−7). Gratifyingly,
the effects observed for the SN2 with CBz-protected 9d
translated well with Boc protected 12. In fact superior intrinsic
O-selectivity was observed.22 Carrying out the reaction with
Cs2CO3 in NMP (∼0.1 M, 20 mL/g concentration) at 60 °C,
afforded 10.6:1 ratio favoring O-alkylation. In addition, while
developing the isolation of 10 and 14 we were very pleased to
see that the N-alkylation adducts 11 were more water-soluble in
the water/NMP layer during th extractve workup, allowing for
further upgrade of the O- vs N-selectivity of the product when
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Scheme 4. Synthesis of biaryl acid 2
Scheme 5. Final coupling and end game for 1
isolating in this manner. On >3-kg scale this observation led to
a 15:1 isolation of 14 in 79% isolated yield. The synthesis of the
chiral fragment 3 was completed with the removal of the Boc
protecting group using trifluoroacetic acid in DCM. At this
stage, extractive workup provided amine 3 in high purity
(Scheme 3).
ditions and coupling agents revealed that using 1-propyl
phosphonic anhydride (T3P)24 provided the desired reactivity
when the reactions were heated to >40 °C and an excess
coupling agent was used. Using 1.25 equiv of biaryl acid 2, 3.4
equiv of T3P with DIPEA in DCM at 44 °C for 48 h provided 1
in 88% assay yield. Charcoal treatment facilitated the final
recrystallization which was performed in isopropyl acetate with
heptane as an antisolvent to increase recovery. Crystalline 1 was
isolated with the desired purity for preclinical and clinical use
(Scheme 5).
Biaryl acid fragment 2 was prepared in a straightforward
manner from the commercially available iodobenzoic acid 15
(Scheme 4). Fisher esterification with methanol was performed
before palladium-catalyzed borylation. The use of pinacol
borane in the latter reaction offered multiple advantages when
compared with bis(pinacolato)diboron: rapid conversion, high
yield, easier workup, better purity profile. The Suzuki−Miyaura
coupling with 2-chloropyrimidine proceeded smoothly with
PdCl2dppf·DCM (3.5 mol %) and aqueous Na2CO3 in 2-
methyltetrahydrofuran (2-MeTHF) at 75 °C. Finally saponifi-
cation with NaOH in 2-MeTHF/water provided biaryl acid 2
which was precipitated from the basic aqueous layer by
acidification with HCl in high recovery and excellent purity.
Using 2-MeTHF as a cosolvent in the biaryl ester hydrolysis
simplified the workup when compared with THF. The three
steps from the methyl benzoate 16 to biaryl acid 2 could
therefore be carried out as a through process without isolation,
thus decreasing the processing time on kilogram scale.
The final amidation was surprisingly challenging. Highly
reactive coupling reagents such as HATU and EDC/HOBT
failed to achieve more than 5% conversion to the desired amide
MK-6096 (1). Activation of acid 2 with oxalyl chloride or
thionyl chloride was difficult due to insolubility of the activated
species in organic solvents. Direct amidation of the methyl ester
of biaryl acid 2 with magnesium, lithium, and aluminum amides
of 3 provided unacceptably low yields of 1 (<50%). While
initial results pointed to issues with acid activation, further
studies showed that the properties of piperidine 3 also
contributed to the low yields. Substituting piperidine 3 with
benzylamine gave significantly better conversions under several
amidation conditions.23 Further screening of reaction con-
CONCLUSION
■
A convergent strategy was utilized to complete a scalable,
chromatography-free synthesis of 1 in nine steps (longest linear
sequence) and 13% overall yield. Highlights of this process
include a highly enantioselective transamination reaction for the
preparation of chiral α-methylpiperidines, a diastereomeric
purity upgrade provided by the crystallization of 8·CSA salt,
and a chemoselective SN2 reaction which allowed for the facile
preparation of the chiral piperidine core of 1. This synthesis has
been carried out on mutli-kilogram scale, supporting the
development of this compound as a treatment for insomnia.
This transamination strategy provides a general approach for
the practical synthesis of chiral lactams from prochiral keto-
esters.25 Additional studies to investigate the scope of this
transformation and improve diastereoselectivity of the lactam
reduction are ongoing and will be reported in due course.
EXPERIMENTAL SECTION
■
2-(3-Oxo-butyl)malonic Acid Dimethyl Ester (5). A
mixture of acetonitrile (20 L), K2CO3 (986 g, 7.13 mol) and
dimethyl malonate (10.1 kg, 76.0 mol) was cooled to 17 °C,
and methyl vinyl ketone (5.00 kg, 71.3 mol) was added over 3 h
at <26 °C. The reaction mixture was stirred for 18 h. It was
partitioned between MTBE (60 L) and water (20 L), and the
aqueous layer was extracted with MTBE (20 L). The combined
organic layers were washed with water (20 L), filtered over
D
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Solka Floc, and concentrated under reduced pressure via direct
distillation of the solution. The crude product was used as such
3354, 3270, 2933, 1638, 1046. HRMS (ESI) m/z calcd for
C7H13NO2 [M + H]+ 144.1019, found 144.1019. Mp 42−44
°C.
1
in the next reaction. H spectra are in complete accord with
literature precedent.26
((3R,6R)-6-Methyl-piperidin-3-yl)methanol D-(+)-Cam-
phorsulfonic Acid Salt (8·CSA). In a 100 L reaction vessel
was charged the crude suspension of lactam 7 (2.07 kg, 14.5
mol, containing 0.6 equiv of iPrOH) in THF (24 L). The
mixture was cooled to −25 °C, and LiAlH4 (2.6 M in THF,
22.2 L, 57.8 mol) was added over 3.5 h, keeping the
temperature below 12 °C. THF (8 L) was added to facilitate
stirring. The mixture was heated to 50 °C and stirred for 12 h.
It was then cooled to −25 °C, and water (2.2 L) was added
over 3 h, keeping the temperature below 10 °C. NaOH (2.2 L,
3.75 M) was added over 1.5 h (16 L THF was added to
facilitate stirring), and finally water (6.6 L) was added over 1 h,
keeping the temperature below 13 °C. The suspension was
cooled to 5 °C and stirred for 1.5 h. The suspension was
filtered over Solka Floc, rinsing with THF (20 L). The filtrate
(6R)-Methyl-6-methyl-2-oxopiperidine-3-carboxylate
(4). In a 100 L Buchi jacketed reactor with overhead stirring
was added 30 °C water (45 L) to which were added Na2HPO4
(852 g, 5.4 mol), D-alanine (7.2 kg, 81 mol), glucose (6.48 kg,
32.4 mol), NAD (22.5 g, 0.034 mol), and PLP (45 g, 0.18 mol).
The pH was adjusted to 7.4 with NaOH and then ATA-117
transaminase (450 g, Biocatalytics cat. # ATA-117, lot
0702D90007), lactate dehydrogenase (9 g, Biocatalytics cat. #
LDH-101, lot 102805CL), and glucose dehydrogenase (45 g,
Biocatalytics cat. # GDH-103, lot 120406MM) and rinsed into
the vessel with water (2.5 L). After all enzymes were in
solution, the keto-diester 5 (4.5 kg, 22.3 mol) was added,
followed by a final water addition (2.5 L). pH control utilizing 5
N NaOH was initiated. The reaction was complete at 31 h but
was stirred until 42 h. To the reaction vessel was added NaCl
(19.4 kg) and 5 N HCl (6.0 L) to adjust the pH to 3.5.
Acetonitrile (20 L) was added and allowed to stir for 10 min.
The agitator was turned off and the reaction mixture allowed to
settle for 1 h. The acetonitrile layer was removed; the aqueous
layer was re-extracted with acetonitrile, and these acetonitrile
layers were combined. The resulting acetonitrile solution was
filtered through Solka Floc and concentrated to remove both
acetonitrile and water. The resulting oil contained high levels of
heterogeneous NaCl. The oil was then dissolved in EtOAc (50
L), filtered, and transferred to a 20 L round-bottom flask and
concentrated under reduced pressure on a rotary evaporator to
an oil (5.5 kg, 94 wt %, 74% yield, 99% ee) and used directly in
1
was assayed by HPLC (1.54 kg, 82% yield, 1.7:1 dr by H
NMR). It was combined with a batch of similar size (total 3.04
kg, 23.5 mol) and charged in a 140 L reaction vessel. The
solution was concentrated under reduced pressure via
distillation, and flushed with THF (20 L) and diluted with
THF to a final volume of 60 L. A solution of D-(+)-CSA (4.37
kg, 18.8 mol) in THF (12 L) was added over 1 h, and stirring
was continued at room temperature for 45 min. MTBE (30 L)
was added over 45 min, the suspension was stirred for 45 min
more, cooled to 2 °C over 45 min, and stirred for 30 min. The
solids were recovered by filtration and rinsed with THF/MTBE
= 1:1 (2 × 18 L) and MTBE (18 L). A white solid (4.46 kg,
52% yield, >40:1 dr) was obtained. An analytical sample of the
free base was obtained; the salt was partitioned between
MeTHF and sat. NaHCO3; the organic layer was washed with
brine, dried over anhydrous MgSO4, and concentrated under
1
the next step. Crude H spectra are consistent with previous
literature reports.27
(6R)-3-Hydroxymethyl-6-methyl-piperidin-2-one (7).
In a 140 L reaction vessel was charged ester 4 (2.81 kg, 16.4
mol) and EtOH (84 L). Calcium chloride (3.65 kg, 32.9 mol)
was added in three portions over 15 min and stirred until
complete dissolution. Cooling was set to keep the internal
temperature below 22 °C for the duration of the reaction.
Sodium borohydride (2.49 kg, 65.7 mol) was added in three
portions over 20 min. The reaction mixture was stirred for 20 h.
It was cooled to 5 °C and quenched by careful addition of 6 N
HCl (11.2 L) over 30 min. It was warmed to room
temperature, stirred for 2 h, and filtered over Solka Floc,
rinsing with EtOH. The filtrate was combined with a second
batch of similar size (14.4 mol ester 4), concentrated under
reduced pressure, and then and solvent switched to water. The
resulting aqueous layer (32 L) was extracted with 1-butanol (53
L, then 2 × 26.5 L). The combined organic layers were washed
with brine (10.5 L) and concentrated under reduced pressure,
solvent switching to water, then iPrOH. The resulting
suspension (∼40 L) was filtered over Solka Floc, rinsing with
iPrOH (2 × 10 L). The filtrate was assayed by HPLC (4.13 kg,
94% assay yield, 1.7:1 dr). The crude solution was solvent
switched to THF to yield a beige suspension. An analytical
sample was prepared by flash chromatography on silica gel
1
reduced pressure. H NMR (500 MHz, CDCl3) 3.44 (dd, J =
10.7, 5.6 Hz, 1 H), 3.36 (dd, J = 10.7, 7.2 Hz, 1 H), 3.25−3.13
(m, 1 H), 2.57−2.49 (m, 1 H), 2.32 (t, J = 11.5 Hz, 1 H), 2.24
(m, 2 H), 1.79−1.75 (m, 1 H), 1.66 (m, 1 H), 1.63−1.55 (m, 1
H), 1.14−0.98 (m, 5 H). 13C NMR (101 MHz, CDCl3) 66.0,
52.3, 50.1, 39.5, 34.0, 27.9, 22.6. IR (neat, cm−1) 3273, 2960,
2922, 2852, 1644, 1443, 1378, 1054. HRMS (ESI) m/z calcd
for C7H15NO [M + H]+ 130.1226, found 130.1230. Mp 88.4−
90.2 °C. [α]20 −5.9 (c 0.010, CH2Cl2).
D
(2R,5R)-2-Methyl-5-(toluene-4-sulfonyloxymethyl)-
piperidine-1-carboxylic Acid tert-Butyl Ester (12). In a
140 L reaction vessel was charged DCM (40 L), piperidine salt
8·CSA (4.19 kg, 11.6 mol), triethylamine (4.84 L, 34.9 mol),
and Boc2O (2.66 kg, 12.2 mol). The mixture was stirred for 3 h.
It was quenched with NH4Cl (40 L, 2 M), and the layers were
cut. The organic layer was washed with brine (20 L, 1/2 sat.),
assayed by HPLC (2.81 kg, 105% assay yield), dried over
anydrous Na2SO4 (200 wt %), and filtered. Most of the crude
solution (2.75 kg, 12.0 mol) was concentrated under reduced
pressure to a volume of 10 L. It was cooled to 0 °C, and
pyridine (5.47 L, 72.6 mol) and TsCl (2.52 kg, 13.2 mol, four
portions over 1 h) were added. The reaction mixture was
warmed to room temperature and stirred for 18 h. It was
partitioned between MTBE (19 L), NH4Cl (20 L, sat.), and
water (10 L). The layers were cut, and the organic layer was
washed with CuSO4·5H2O (20 L, then 10 L), NaHCO3 (10 L,
sat.), and brine (10 L, 1/2 sat.). It was filtered through a pad of
silica gel (1.5 kg), rinsed with MTBE (10 L), and assayed by
HPLC (4.28 kg, 93% assay yield). An analytical sample was
1
(gradient from EtOAc only to 5% MeOH/EtOAc). H NMR
(500 MHz, DMSO-d6, 60 °C) 7.30−7.16 (m, 1 H), 4.45−4.37
(m, 1 H), 3.67−3.49 (m, 2 H), 3.45−3.30 (m, 1 H), 2.25−2.12
(m, 1 H), 1.91−1.66 (m, 2 H), 1.60−1.39 (m, 1 H), 1.32−1.20
(m, 1 H), 1.12−1.07 (m, 3 H). 13C NMR (126 MHz, DMSO-
d6, 60 °C) 172.4, 172.3, 62.7, 62.6, 62.5, 48.6, 48.5, 47.5, 43.4,
43.2, 30.6, 27.9, 23.8, 22.9, 22.8, 22.6, 21.2. IR (neat, cm−1)
E
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obtained by flash chromatography on silica gel (gradient from
111.6, (d, JCF = 4.7 Hz), 69.5, 52.2, 50.3, 36.6, 34.1, 28.2, 22.7.
IR (neat, cm−1): 2930, 1486, 1366, 1224, 826. HRMS (ESI) m/
z calcd for C12H17FN2O [M + H]+ 224.1325, found 224.1342.
10% to 70% EtOAc/hexanes). The crude solution was solvent
1
switched to NMP and used as such in the next reaction. H
NMR (500 MHz, CD3CN) 7.76 (d, J = 7.8 Hz, 2 H), 7.42 (d, J
= 7.7 Hz, 2 H), 4.16 (br s, 1 H), 4.03−3.95 (m, 1 H), 3.89−
3.82 (m, 1 H), 3.76 (d, J = 14.2 Hz, 1 H), 2.98 (d, J = 14.3 Hz,
1 H), 2.42 (s, 3 H), 2.02−1.88 (m, 2 H), 1.83−1.71 (m, 1 H),
1.55−1.45 (m, 1 H), 1.36 (s, 9 H), 1.25−1.15 (m, 1 H), 1.06
(d, J = 6.8 Hz, 3 H). 13C NMR (126 MHz, CH3CN) 155.7,
146.2, 133.8, 131.0, 128.7, 79.7, 71.4, 47.2, 39.0, 33.8, 28.6,
25.9, 21.7, 20.5, 16.4. IR (neat, cm−1) 2922, 1691, 1360, 1172.
HRMS (ESI) m/z calcd for C19H29NO5S [M + Na]+ 406.1664,
[α]20 +3.1 (c 3.0, CH2Cl2).
D
2-Iodo-5-methyl-benzoic Acid Methyl Ester (16). In a
100 L reaction vessel was charged MeOH (50 L), 2-iodo-5-
methylbenzoic acid (5.85 kg, 22.3 mol), and conc. sulfuric acid
(595 mL, 11.2 mol). The mixture was heated to 65 °C and
stirred for 18 h. It was cooled to 16 °C, and 10 N NaOH (850
mL, 21.9 mol) was added over 10 min until pH 5−6 was
obtained. Caution: a pH over 9 can result in saponification
during the workup. The solution was then concentrated to
about 16 L, and the resulting suspension was partitioned
between IPAc (40 L), water (4 L), NaHCO3 (10 L, 5 wt %),
and brine (10 L, 15 wt %). The layers were cut, and the
aqueous layer was extracted with IPAc (20 L). The combined
organic layers were washed with brine (10 L, 15 wt %) and
assayed by HPLC (6.06 kg, 98% assay yield). The crude
solution was solvent switched to 2-MeTHF and used as such in
the next reaction.An analytical sample was obtained by
found 406.1663. Mp 64−65 °C. [α]20 −27.1 (c 1.0, CHCl3).
D
(2R,5R)-5-(5-Fluoro-pyridin-2-yloxymethyl)-2-methyl-
piperidine-1-carboxylic Acid tert-Butyl Ester (14). In a
100 L reaction vessel was charged the crude solution of
piperidine 12 (3.23 kg, 8.42 mol) in NMP (65 L), 5-fluoro-2-
hydroxypyridine (1.19 kg, 10.5 mol), and Cs2CO3 (7.37 kg,
22.6 mol). The mixture was heated to 60 °C and stirred for 26
h. It was cooled to 15 °C before addition of water (65 L) over 1
h, keeping the temperature below 28 °C. The solution was
extracted with MTBE (65 L). The organic layer was washed
with 10 wt % LiCl (2 × 32 L) and brine (2 × 32 L, 1/2 sat.). It
was assayed by HPLC (2.16 kg, 79% assay yield). The crude
solution was solvent switched to DCM and used as such in the
next reaction. An analytical sample was obtained by flash
chromatography on silica gel (gradient from 10% to 70%
EtOAc/hexanes). 1H NMR (400 MHz, acetone-d6) 8.01 (d, J =
3.1 Hz, 1 H), 7.54 (m, 1 H), 6.82 (dd, J = 9.1, 3.6 Hz, 1 H),
4.37−4.24 (m, 2 H), 4.13 (dd, J = 10.6, 6.3 Hz, 1 H), 3.99 (d, J
= 13.9 Hz, 1 H), 3.09 (dd, J = 13.9, 3.9 Hz, 1 H), 2.15−2.07
(m, 1 H), 1.96−1.73 (m, 2 H), 1.56−1.48 (m, 1 H), 1.33 (m,
10 H), 1.14 (d, J = 6.9 Hz, 3 H). 13C NMR (101 MHz, acetone-
d6) 161.2, 156.3 (d, JCF = 243 Hz), 155.4, 133.7 (d, JCF = 26
Hz), 127.5 (d, JCF = 21 Hz), 112.5 (d, JCF = 5 Hz), 79.0, 66.7,
47.0, 39.5, 33.8, 28.4, 26.3, 21.1, 16.4. IR (neat, cm−1) 2972,
2937, 1687, 1486, 1467, 1366, 1266, 1227, 1150. HRMS (ESI)
m/z calcd for C17H25FN2O3 [M + H]+ 325.1922, found
1
chromatography on silica gel (10% EtOAc/Hex). H NMR
(500 MHz, CDCl3) 7.84 (d, J = 8.1 Hz, 1 H), 7.62 (d, J = 2.1
Hz, 1 H), 6.97 (dd, J = 8.1, 2.1 Hz, 1 H), 3.97−3.86 (m, 3 H),
1
2.33 (s, 3 H). The H NMR spectra obtained are in complete
accord with literature precedent.28
5-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)benzoic Acid Methyl Ester (17). In a 100 L reaction
vessel was charged the crude solution of iodide 16 (5.91 kg,
21.4 mol) in 2-MeTHF (35 L) and triethylamine (8.94 L, 64.1
mol). The solution was degassed with N2, and pinacol borane
(4.65 L, 32.1 mol) was added over 15 min while maintaining
the N2 purge. Degassing was continued for 10 min. Trio-
tolylphosphine (325 g, 1.07 mol) and palladium(II) acetate
(120 g, 0.534 mol) were added. The reaction mixture turned
black, and a slow exotherm to 60 °C was observed. The
reaction was heated to 77 °C and stirred for 45 min. It was
cooled to room temperature before aqueous NH4Cl (26 wt %)
was added over 60 min (to control gas evolution and
exotherm). The addition resulted in the formation of a black
precipitate. The supernatant was transferred to an extractor
containing water (40 L). The remaining black slurry was
filtered over Solka Floc, rinsing with MTBE (20 L). The filtrate
was added to the extractor. The layers were cut, and the organic
layer was assayed by HPLC (4.45 kg, 75% assay yield). The
crude solution was solvent switched to 2-MeTHF and used as
such in the next reaction. An analytical sample was obtained by
chromatography on silica gel (gradient from 10% to 40%
325.1921. [α]20 −11.0 (c 0.010, CH2Cl2).
D
5-Fluoro-2-((3R,6R)-6-methyl-piperidin-3-ylmethoxy)-
pyridine (3). In a 50 L reaction vessel was charged the crude
solution of Boc-piperidine 14 (2.15 kg, 6.63 mol) in DCM
(11.4 L). It was cooled to −2 °C, and TFA (5.5 L, 71.4 mol)
was added over 40 min, keeping the temperature below 5.5 °C.
The reaction mixture was warmed to room temperature and
stirred for 3.5 h. It was concentrated under reduced pressure,
and the resulting oil was added to a cooled, stirring solution of
3 N NaOH (28 L) in a 100 L extractor. MTBE (30 L) was
added, and the layers were cut. The organic layer was extracted
with 2 N HCl (30 L, then 10 L). The combined aqueous layers
were cooled to 9 °C, and 10 N NaOH was added until pH
reached 13 (temperature reaches 21 °C). This solution was
extracted with MTBE (25 L, then 10 L) and assayed by HPLC
(1.46 kg, 98% yield, >99.7% purity). The crude solution was
solvent switched to DCM and used as such in the next reaction.
An analytical sample was obtained by concentration under
reduced pressure. 1H NMR (400 MHz, CDCl3) 7.96 (d, J = 3.1
Hz, 1 H), 6.69 (dd, J = 9.0, 3.6 Hz, 1 H), 4.11 (dd, J = 10.5, 5.5
Hz, 1 H), 4.00 (dd, J = 10.5, 7.2 Hz, 1 H), 3.28−3.22 (m, 1 H)
2.63−2.54 (m, 1 H), 2.45 (t, J = 11.4 Hz, 1 H), 1.97−1.87 (m,
2 H), 1.74−1.68 (m, 1 H), 1.18−1.09 (m, 2 H), 1.07 (d, J = 6.3
1
EtOAc/Hex). H NMR (500 MHz, CDCl3) 7.75 (s, 1H), 7.40
(d, J = 7.5 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 3.90 (s, 3 H),
2.37 (s, 3 H), 1.41 (s, 12 H). 13C NMR (125 MHz, CDCl3)
168.6, 139.0, 133.6, 132.5, 132.3, 129.4, 83.9, 52.2, 24.9, 21.3
(one overlapping peak, as no other peaks are detected even
with prolonged scans). IR (neat, cm−1) 2980, 1718, 1347, 1058,
857. HRMS (ESI) m/z calcd for C15H21BO4 [M]+ 276.1533,
found 276.1543. Mp 62.0−64.0 °C.
5-Methyl-2-pyrimidin-2-yl-benzoic Acid Methyl Ester
(18). In a 100 L reaction vessel was charged the crude solution
of pinacol boronate 17 (4.38 kg, 15.8 mol) in 2-MeTHF (35
L), 2-chloropyrimidine (2.18 kg, 19.0 mol), Na2CO3 (5.04 kg,
47.5 mol), and water (11.7 L). The thick slurry was degassed
with N2 for 40 min after which PdCl2(dppf)·CH2Cl2 (518 g,
0.634 mol) was added. The reaction mixture was heated to 74
°C and stirred for 16 h. It was cooled to room temperature.
Hz, 3 H). 13C NMR (101 MHz, CDCl3) 160.1, 155.3 (d, JCF
246.8 Hz), 133.0 (d, JCF = 27.2 Hz), 126.5 (JCF = 21.2 Hz),
=
F
dx.doi.org/10.1021/op3002678 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Water (12 L) and MTBE (24 L) were added and stirring was
continued for 10 min. The suspension was filtered over Solka
Floc, rinsing with MTBE (4 L), water (2 × 4 L), and MTBE (4
L) again. The layers were cut, and the aqueous layer was
extracted with MTBE (21.5 L). The organic layer was assayed
by HPLC (2.76 kg, 76% assay yield). It was treated with Darco
KB-G (1.26 kg) for 2 h and filtered over Solka Floc, rinsing
with MTBE (3 × 10 L). The solution was assayed by HPLC
(2.38 kg, 86% recovery, 66% overall yield, 427−493 ppm Pd
and 882−934 ppm Fe). The crude solution was solvent
switched to 2-MeTHF and used as such in the next reaction. An
analytical sample was obtained by concentration under reduced
brine 15% (10 L). The organic fractions (quantitative HPLC
assay at 1.65 kg) were then treated with ∼50 wt % of Darco KB
(750g) for 1.75 h, then filtered on Solka Floc, and rinsed with
MTBE (10 mL/g, 16.5 L, 1.559 kg, 94.5% recovery). The crude
MTBE solution was charged through a 1 μm in-line filter, in a
visually clean and dry 50 L RBF equipped with a mechanical
stirrer, a thermocouple, a reflux condenser, and a nitrogen inlet.
The reaction mixture was solvent-switched to IPAc (7.5L). The
reaction mixture was warmed to 75 °C which dissolved as solids
and then cooled to room temperature slowly and seeded at 45
°C with 1 (18 g), stirred overnight (16 h) at room temperature
then heptane was added (9.5 L) over 60 min. The reaction
mixture was aged for 1 h before cooling to 5 °C and stirred for
30 min. The suspension was then filtered and rinsed with
IPAC/heptane (2 × 5L of cold 15% IPAc) and heptane (10 L).
The residual beige solid was dried under a flow of nitrogen for
18 h (the product was found to be dry with <0.3 wt % of
solvents); 1.2 kg of 1 was isolated as a light-beige solid (99.4
LCAP, >99.5% ee, >99.5% dr, Pd level of 8 ppm, and KF of
0.1). 1H spectra are in complete accord with literature
precedent.5
1
pressure. H NMR (500 MHz, CDCl3) 8.78 (d, J = 4.9 Hz, 2
H), 7.97 (d, J = 7.9 Hz, 1 H), 7.51 (s, 1 H), 7.39 (d, J = 8.0 Hz,
1 H), 7.19 (t, J = 4.9 Hz, 1 H), 3.75 (s, 3 H), 2.44 (s, 3 H). 13
C
NMR (126 MHz, CDCl3) 170.2, 165.4, 156.8, 140.1, 135.0,
132.8, 131.4, 129.9, 129.5, 118.9, 52.1, 21.2. IR (neat, cm−1)
2953, 1725, 1556, 1417, 1305, 807. HRMS (ESI) m/z calcd for
C13H12N2O2 [M]+ 228.0899, found 228.0900.
5-Methyl-2-pyrimidin-2-yl-benzoic Acid (2). A 50 L
reaction vessel was charged with the crude solution of biaryl
ester 18 (2.37 kg, 10.4 mol) in 2-MeTHF (15 L), water (20 L),
and 10 N NaOH (2.60 L, 26.0 mol). The reaction mixture was
heated to 72 °C and stirred for 1.5 h. It was cooled to room
temperature and partitioned between water (4 L) and MTBE
(10 L). The layers were cut, and the aqueous layer was washed
MTBE (2 × 10 L). It was cooled to 7 °C and acidified to pH 1
with 12 N HCl (2.3 L), keeping the temperature below 10 °C.
The precipitate was recovered by filtration and rinsed with
water (2 × 7 L, 0 °C), 15% MTBE/heptane (7 L, 0 °C), 15%
toluene/heptane (7 L, 0 °C), MTBE (3.5 L), and heptane (2 ×
7 L). A light-beige solid was obtained (2.15 kg, 97% yield,
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*Louis-Charles.Campeau@merck.com.
■
Notes
1
The authors declare no competing financial interest.
99.2% purity, 264 ppm Pd and 19.7 ppm Fe). H NMR (500
MHz, DMSO-d6) 12.65 (s, 1 H), 8.85−8.82 (m, 2 H), 7.78 (dd,
J = 7.9, 2.3 Hz, 1 H), 7.49−7.37 (m, 3 H), 2.40 (s, 3 H). 13C
NMR (101 MHz, DMSO-d6) 170.1, 165.1, 157.1, 139.4, 135.1,
134.2, 130.8, 129.9, 129.0, 119.4, 20.7. IR (neat, cm−1) 1702,
1575, 1417, 1204, 784. HRMS (ESI) m/z calcd for
C12H10N2O2 [M]+ 214.0742, found 214.0740. mp 227.6−
228.1 °C (followed by rapid degradation).
ACKNOWLEDGMENTS
■
We thank Claude Briand, Ravi Sharma, Wayne Mullett, Richard
Desmangles, and Dean Hutchings for analytical support. We
also thank Paul Coleman and the members of the medicinal
chemistry team for providing valuable intermediates for
chemical development.
((2R,5R)-5-(((5-Fluoropyridin-2-yl)oxy)methyl)-2-
methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)-
phenyl)methanone (1). Amine 3 (1 kg, 4.46 mol) was
charged along with DCM (11 L) in a 50 L flask equipped with a
thermocouple and mechanical stirrer. DIPEA (2 L, 11.45 mol)
was added, and then the biaryl acid 2 (1.22 kg, 5.67 mol) was
added to this stirring solution. This solution was cooled with an
ice bath (12 °C). To this stirring solution was added T3P (7.87
L, 13.38 mol) through an addition funnel at <21 °C over 1 h.
Once addition was completed, the reaction became yellow and
heterogeneous. To facilitate stirring DCM (2 L) was added.
The reaction was heated to 44 °C and aged at this temperature
overnight. After 17 h the reaction was not complete, and T3P
(1.1 L, 1.870 mol) was added to accelerate conversion. The
next day (42 h) the reaction was deemed complete by HPLC
and was cooled in an ice bath to 4 °C. Water (20 L) was added,
keeping the reaction temperature <17 °C. This mixture was
then stirred at room temperature for 30 min. Then the mixture
was transferred into a 50 L extractor charged with MTBE (20
L). The flask was rinsed with an additional water (2 L) and
MTBE (4 L). The layers were cut, and the organics were
washed with 1 N NaOH (20 L) and once more with 1 N
NaOH (10 L). Finally, the organics were washed twice with
REFERENCES
■
(1) (a) Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R.
M.; Tanaka, H.; Williams, S. C.; Richarson, J. A.; Kozlowski, G. P.;
Wilson, S.; Arch, J. R. S.; Buckingham, R. E.; Haynes, A. C.; Carr, S. A.;
Annan, R. S.; McNulty, D. E.; Liu, W.-S.; Terrett, J. A.; Elshourbagy,
N. A.; Bergsma, D. J.; Yanagisawa, M. Cell 1998, 92, 573−585. (b) de
Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X.; Foye, P. E.; Danielson, P.
E.; Fukuhara, C.; Battenberg, E. L.; Gautvik, V. T.; Bartlett, F. S., II;
Frankel, W. N.; van den Pol, A. N.; Bloom, F. E.; Gautvik, K. M.;
Sutcliffe, J. G. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 322−327.
(2) (a) Smart, D.; Jerman, J. C. Pharmacol. Ther. 2002, 94, 51−61.
(b) Baumann, C. R.; Bassetti, C. L. Lancet Neurol. 2005, 4, 673−682.
(3) (a) Nishino, S. Sleep Med. 2007, 8, 373−399. (b) Nishino, S.;
Okuro, M.; Kotorii, N.; Anegawa, E.; Ishimaru, Y.; Matsumura, M.;
Kanbayashi, T. Acta Physiol. 2010, 198, 209−222.
(4) (a) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.;
McGaugher, G. B.; Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.;
Bednar, R. A.; Lemaire, W.; Bruno, J. G.; Reiss, D. R.; Harrell, C. M.;
Murphey, K. L.; Garson., S. L.; Doran, S. M.; Prueksaritanont, T.;
Anderson, W. B.; Tang, C.; Roller, S.; Cabalu, T. D.; Cui, D.; Hartman,
G. D.; Young, S. D.; Koblan, K. S.; Winrow, C. J.; Renger, J. J.;
Coleman, P. J. J. Med. Chem. 2010, 53, 5320−5332. (b) Bergman, J.
M.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A; Reiss, D. R.; Ransom,
R. W.; Harrell, C. M.; Pettibone, D. J.; Lemaire, W.; Murphy, K. L.; Li,
G
dx.doi.org/10.1021/op3002678 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
C.; Prueksaritanont, T.; Winrow, C. J.; Renger, J. J.; Koblan, K. S.;
Hartman, G. D.; Coleman, P. J. Bioorg. Med. Chem. Lett. 2008, 18,
1425−1430. (c) Whitman, D. B.; Cox, C. D.; Breslin, M. J.; Brashear,
K. M.; Schreier, J. D.; Bogusky, M. J.; Bednar, R. A.; Lemaire, W.;
Bruno, J. G.; Hartman, G. D.; Reiss, D. R.; Harrell, C. M.; Kraus, R. L.;
Li, Y.; Garson, S. L.; Doran, S. M.; Prueksaritanont, T.; Li, C.; Winrow,
C. J.; Koblan, K. S.; Renger, J. J.; Coleman, P. J. Chem. Med. Chem.
2009, 4, 1069−1074.
(5) Coleman, P. J.; Schreier, J. D.; Cox, C. D.; Breslin, M. J.;
Whitman, D. B.; Bogusky, M. J.; McGaughey, G. B.; Bednar, R. A.;
Lemaire, W.; Doran, S. M.; Fox, S. V.; Garson, S. L.; Gotter, A. L.;
Harrell, C. M.; Reiss, D. R.; Cabalu, T. D.; Cui, D.; Prueksaritanont,
T.; Stevens, J.; Tannenbaum, P. L.; Ball, R. G.; Stellabott, J.; Young, S.
D.; Hartman, G. D.; Winrow, C. J.; Renger, J. J. ChemMedChem 2012,
7, 415.
(23) Reaction between benzylamine and biaryl acid 2 with HATU
afforded >75% conversion to the benzyl amide. Trimethylaluminum-
mediated reactions of benzylamine with 18 also proceeded smoothly.
(24) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. 1980, 19,
133−134.
(25) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.
A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
(26) Saidi, M. R.; Azizi, N.; Akbari, E.; Ebrahimi, F. J. Mol. Catal. A:
Chem. 2008, 292, 44−48.
(27) Dubnash, N. P.; Mangu, N. K.; Satyam, A. Synth. Commun.
2004, 1791.
(28) Moss, R. A.; Chung, Y.-C. J. Org. Chem. 1990, 55, 2064−2069.
(6) Campeau, L.-C.; Hughes, G.; Gauvreau, D.; Girardin-Rondeau,
M.; Mellon, C.; Moore, J. C.; O’Shea, P.; Ouellet, S. G. Process for the
preparation of an orexin receptor antagonist. WO/2009/143033 A1,
2009.
(7) Previous preparation of 3, relied on chiral chromatographic
separation of a racemic mixture of diastereoisomers via preparative
HPLC. See ref 5.
(8) A similar strategy was recently disclosed for α-arylpiperidinones,
see: (a) Cheemala, M. N.; Knochel, P. Org. Lett. 2007, 9, 3089. For
other asymmetric synthesis of D-lactams, see: (b) Burke, A. J.; Davies,
S. G.; Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A. D.;
Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387.
(c) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000, 2,
1041. (d) Davis, F. A.; Szewczyk, J. M. Tetrahedron Lett. 1998, 39,
5951.
(9) For a precedent using ethyl malonate, see: Dubnash, N. P.;
Mangu, N. K.; Satyam, A. Synth. Commun. 2004, 1791.
(10) Bornscheuer, U. T.; Huisman, G. W.; Kazlauskas, R. J.; Lutz, S.;
Moore, J. C.; Robins, K. Nature 2012, 485, 185.
(11) For a recent application of transaminase in the manufacture of
pharmaceuticals, see: Savile, C. K.; Janey, J. M.; Mundorff, E. C.;
Moore, J. C.; Tam, S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz,
F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. Science
2010, 329, 305.
(12) Shin, J.-S.; Kim, B.-G. Biotechnol. Bioeng. 1999, 65, 206.
(13) Lidstroem, K.-O. PharmaChem 2007, 6, 5.
(14) Koszelewski, D.; Lavandera, I.; Clay, D.; Rozzell, D.; Kroutil, W.
Adv. Synth. Catal. 2008, 350, 2761.
(15) Truppo, M. D.; Rozzell, J. D.; Turner, N. J. Org. Process Res. Dev.
2010, 14, 234−237.
(16) This reaction is precedented on a similar substrate in MeOH,
see: Klutchko, S.; Hoefle, M. L.; Smith, R. D.; Essenburg, A. D.;
Parker, R. B.; Nemeth, V. L.; Ryan, M. J.; Dugan, D. H.; Kaplan, H. R.
J. Med. Chem. 1981, 24, 104−109. Caution! When using methanol or
water as a co-solvent, a delayed exotherm and sudden gas evolution
were observed on a few instances (gram-scale reactions). The
reaction can safely be run in EtOH, keeping the temperature <22 °C
for the duration of the reaction.
(17) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; New
York: Wiley, 1967; pp 583−584.
(18) Hughes, D. L. The Mitsunobu Reaction. Org. React. 2004, 335−
656.
(19) For detailed discussion of pyridone alkylation, see: Breugst, M.;
Mayr, H. J. Am. Chem. Soc. 2010, 132, 15380 and references therein.
(20) The medicinal chemistry team had prepared significant amounts
of the CBz-8 which was graciously provided for further study by our
team. For its preparation, see ref 5.
(21) Varying base and pyridone stoichiometry did not influence the
O- vs N-selectivity.
(22) We currently do not fully understand the effect of the protecting
group on the selectivty but hypothesize that influence of the chair
conformation of the ring by the protecting group might play a role in
increasing selectivity.
H
dx.doi.org/10.1021/op3002678 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX