Development of a total telescoped synthesis of a renin inhibitor containing 3,4,5-substituted piperidine with sterically hindered amide bonds

Article abstract of DOI:10.1021/op500116w

A telescoped synthesis for the manufacturing of a renin inhibitor containing 3,4,5-substituted piperidine with sterically hindered amide bonds via a five-step synthetic route is described. Highlights of this scalable synthesis include: (1) the byproduct-c

Full text of DOI:10.1021/op500116w

Article
pubs.acs.org/OPRD
Development of a Total Telescoped Synthesis of a Renin Inhibitor
Containing 3,4,5-Substituted Piperidine with Sterically Hindered
Amide Bonds
Wen-Chung Shieh,* Zhengming Du, Hongyong Kim, Yugang Liu, and Mahavir Prashad
Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936,
United States
ABSTRACT: A telescoped synthesis for the manufacturing of a renin inhibitor containing 3,4,5-substituted piperidine with
sterically hindered amide bonds via a five-step synthetic route is described. Highlights of this scalable synthesis include: (1) the
byproduct-controlled amidation protocol using Ghosez’s reagent in the presence of a mild acid scavenger for the formation of the
first sterically hindered amide bond; (2) the chemoselective hydrolysis of a sterically hindered ester; (3) an efficient amidation
reaction employing a soluble carbodiimide leading to the second sterically hindered amide bond; (4) filtration of the fumarate
salt of the final drug substance, being the only necessary isolation step throughout the total synthesis. Without the necessity of
isolating any intermediates, this telescoped process conserved equipment usage, consumed less solvents, and minimized process
waste generation, energy consumption, personnel exposure, and environmental impact. It furnished kilogram quantities of high-
quality active pharmaceutical ingredients.
controlled to acceptable levels after each single transformation.
We report herein a five-step telescoped process that was
scalable for the synthesis of the fumerate salt of 1 in kilogram
quantities in high efficiency.
INTRODUCTION
Recently, Novartis developed a 4-hydroxy-3,5-substituted
piperidine (1, Figure 1) as a new class of highly efficacious
■
RESULTS AND DISCUSSION
■
Amidation of Sterically Hindered Amine and Carbox-
ylic Acid. The telescoped synthesis for 1 started with the
formation of 4 from sterically hindered amine 2 and carboxylic
acid 3. Amidation reactions involving sterically hindered amines
or carboxylic acids, respectively, have been challenging tasks
since racemization and/or side reactions are common
competing pathways. These resulted in inefficient conversion,
unreacted starting materials, or the formation of byproducts
that often cannot be separated readily from the desired
molecule. Several effective methodologies have been reported
for the synthesis of sterically hindered amides with good
efficiency.2 However, after assessing the handling,2a cost,2b,c and
commercial availability2d,e of coupling reagents utilized by these
methods, we decided to try something different for the
synthesis of 4. Ghosez reported an efficient method for the
synthesis of acyl chlorides under mild conditions employing 1-
chloro-N,N-2-trimethyl-1-propenylamine 8 (Ghosez’s re-
agent).3 This reagent is inexpensive and commercially available
and has been utilized for the synthesis of several sterically
hindered amides in excellent yields.4 To develop a telescoped
process for the synthesis of 1, it was critical to attain good
quality of every single intermediate so that it can be used for
the next step without further purification. Since Ghosez’s
reagent generates a water-soluble byproduct (N,N-dimethyli-
Figure 1. A renin inhibitor.
oral direct renin inhibitor.1 To probe its therapeutic potentials
in humans, we needed to develop a facile and practical synthesis
that allows the production of kilogram quantities of this active
pharmaceutical ingredient (API) for the support of clinical
trials. Since 1 consists of three fragments linked by two
sterically hindered amide bonds, it was obvious that connecting
them sequentially through an applicable amidation method-
ology was a logical approach (Scheme 1). This strategy was
already employed by medicinal chemists, who developed a
linear, four-step route for the synthesis of 1 (Scheme 2).1 To
employ this route for kilogram-scale manufacturing, we had to
overcome several drawbacks.
The most challenging issue was to avoid several chromato-
graphic purifications that were employed previously for each of
the intermediates 4, 5, and 7. Because the physical states of all
intermediates (4, 5, and 7) are noncrystalline, the possibility of
using crystallization−filtration as unit operations to obtain high-
purity products was ruled out. Changing the sequence of the
synthetic route involving the same building blocks was not
considered, as this approach would still go through noncrystal-
line intermediate 7. We therefore envisaged developing a
telescoped synthesis from starting materials to the final drug
substance. To achieve this goal, the impurity profiles must be
Special Issue: Continuous Processes 14
Received: April 8, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/op500116w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Scheme 1. Retrosynthetic analysis of 1
a
Scheme 2. Initial research synthesis of 1
a
Reagents and conditions: (a) Ghosez reagent, CH2Cl2, 0−25 °C, chromatography; (b) 2.5 equiv of LiOH, THF, 0 °C, chromatography; (c) EDC−
HCl, HOAt, Et3N, CH2Cl2, 25 °C, chromatography; (d) 4 N HCl, dioxane, 25 °C.
sobutyramide 9, Scheme 3) that can easily be separated from
the product by a simple aqueous work-up procedure, we
the acid scavenger were unsatisfactory. We observed the
formation of three impurities, as suggested by LC-MS analyses:
10 (7%), 11, and 12 (11 plus 12, 23%) (Scheme 4). As a result,
the assay of 4 was determined to be only 70%, which was not
acceptable. We subsequently performed a series of experiments
intended to identify a protocol that could minimize impurity
contents.
Scheme 3. Ghosez’s reagent 8 for amide synthesis
1
As revealed by a H NMR study, mixing acid 3 with 8 in
CD3CN in the absence of a base led to a rapid and clean
formation of acyl chloride 3c (Scheme 5). No impurity was
detected until amine 2 and Hunig’s base were subsequently
̈
added. Based on these observations, we postulated that
impurities 10, 11, and 12 presumably were generated through
the elimination and Michael addition pathways from an in situ
intermediate 4b (Scheme 6). The elimination reaction may be
promoted by the Ghosez’s reagent 85 and enhanced by an acid
probed whether 8 was an ideal coupling reagent for the
formation of 4 without generating unacceptable impurity
profiles.
The results of our initial attempts to synthesize 4 from 2 and
3 in acetonitrile and by employing 8 as the coupling reagent in
the presence of N,N-diisopropylethylamine (Hunig’s base) as
scavenger such as Hunig’s base.
̈
̈
Scheme 4. Synthesis of sterically hindered amide 4
B
dx.doi.org/10.1021/op500116w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Scheme 5. Plausible mechanism for the amidation reaction employing Ghosez’s reagent
Scheme 6. Postulated mechanism for the formation of impurities 10, 11, and 12
We postulated that a milder base whose pKa (of the
respective conjugated acid) is marginally greater than that of
the conjugated acid 3e formed in situ (Scheme 5) would be still
strong enough to function as an acid scavenger but, on the
other hand, weak enough to avoid the undesired elimination
reactions leading to impurities 10, 11, and 12. Since the
calculated pKa value of 2a was reported to be 6.89 (Figure 2)6
in the total level of impurities (10, 11, and 12) from 30% to
13% when N-methylmorpholine (pKa 7.58) was utilized (Table
1, entry 2). Employing 2-N,N-dimethylaminopyridine (pKa
7.04), we were able to obtain an excellent yield (98.4%) of 4
containing trace amounts (1.6% total) of impurities (Table 1,
entry 3). It is noteworthy that the quality of 4, after aqueous
work-up, met our quality specifications and could be used in the
next reaction step without any further purification. This
protocol was reproducible on plant-scale.
Chemoselective Hydrolysis. Our initial effort to synthe-
size 5 by hydrolyzing the ester functionality of 4 with the
following protocol, 1.0−1.1 equiv of LiOH/THF−H2O 1:1/
THF/0 °C, was problematic. Under these conditions,
hydrolysis of both the ester and the amide group took place,
which resulted in the formation of the undesired diacid 5b
(20%). Being unsatisfied with this uncontrolled hydrolysis
reaction, we committed to identifying alternative conditions
that suppress hydrolysis of the amide bond of 4. The latter is
presumably caused by the presence of the large excess of
lithium hydroxide, which could trigger further hydrolysis driven
by the release of a conjugated species 5d from the tetrahedron
Figure 2. Structures of 2a and 3e.
and its structure is analogous to that of 3e, we investigated the
impacts of a couple of bases whose pKa values are slightly
greater than 6.89 and basicity lower in magnitudes than Hunig’s
̈
base (pKa 10.98). We were pleased to see a significant decline
a
Table 1. Impact of basicity of the acid scavenger on the formation of impurities
b
b
b
b
entry
base
Hunig’s base
pKa5
% 2
% 10
% 11 plus 12
% 4
1
2
3
10.98
7.58
7.04
0
10
0
7
23
6
70
87
̈
N-methylmorpholine
7
2-N,N-dimethylaminopyridine
0.4
1.2
98.4
a
b
Reaction was performed in acetonitrile. Determined by HPLC analysis.
C
dx.doi.org/10.1021/op500116w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Scheme 7. Postulated mechanism for the formation of diacid 5b
intermediate 5c (Scheme 7). We speculated that appropriate
control of lithium hydroxide concentration to minimum at any
given time would allow a chemoselective hydrolysis of the ester
bond.
fully avoided, as no diacid 5b had been detected during the
course of saponification reaction. This can be achieved only if
the end-point of saponification was carefully monitored by
HPLC to avoid further amide hydrolysis. The clean and
efficient conversion of 4 to 5 contributed to a successful
operation in the plant affording 5 with 99% purity without the
requirement of further purification.
Karlsson et al. reported a protocol for ester hydrolysis
employing relatively mild conditions: 1 equiv of ester substrate/
3 equiv of Et3N/10 equiv of LiBr/CH3CN containing 2 vol %
of water/25 °C.7 This methodology was not only applicable to
a variety of esters with excellent yields but also can
chemoselectively hydrolyze esters in the presence of an amide
functionality. We hypothesized that Karlsson’s protocol
probably generates low concentrations of lithium hydroxide
in situ at any given time (Scheme 8), which attacks
preferentially the carbonyl group of esters relative to that of
an amide attributing to a lower activation required for the
former reaction.
Formation of the Second Sterically Hindered Amide
Bond. To install the second amide bond, starting from
carboxylic acid 5 and amine 6, the medicinal chemists utilized
an amidation protocol: N-(3-(dimethylamino)propyl)-N′-ethyl-
carbodiimide hydrochloride (EDC)8 as the coupling reagent
and 1-hydroxy-7-azabenzotriazole (HOAt) as the promoter.
One advantage of this methodology is the formation of an acyl
urea byproduct that is water-soluble and can be easily separated
from the product by aqueous work-up. Therefore, we decided
to keep EDC but to replace the hazardous HOAt (explosion
potential) by a safer promoter 1-hydroxybenzotriazole (HOBt),
which had been used successfully for an amide synthesis in our
pilot plant.9 Employing EDC−HOBt for the amidation reaction
involving 5 and 6, we were able to synthesize sterically hindered
amide 7 in 99% yield (determined by HPLC) with >98% purity
in our plant. Amide 7 was produced as a solution in isopropyl
acetate and used for the final step without further purification.
End-Game Synthesis and Fumarate Salt Formation.
To synthesize the desired drug substance, the solution of
penultimate compound 7 in isopropyl acetate was treated with
6 N aqueous solution of hydrochloric acid. This biphasic system
Scheme 8
After a moderate optimization of Karlsson’s protocol, we
were able to selectively hydrolyze the ester group in 99% yield
(determined by HPLC) by employing the following conditions:
1 equiv of 4/5 equiv of Et3N/10 equiv of LiBr/5 equiv of H2O/
CH3CN/25 °C/6 h. Hydrolysis of the amide bond of 4 was
Scheme 9. Total telescoped synthesis of 1
D
dx.doi.org/10.1021/op500116w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
required no phase-transfer catalyst and efficiently removed the
Boc protecting group from 7 to furnish 1 in 99% yield
(determined by HPLC) with >98% purity as a solution in ethyl
acetate, after work-up and solvent exchange. Since the fumarate
salt 1f (Scheme 9) is the required active pharmaceutical
ingredient, the final synthesis required the conversion of free
base 1 to this organic salt. Accordingly, the solution of 1 in
ethyl acetate was reacted with a solution of fumaric acid in
ethanol. This binary-solvent system was selected since it can
produce a fumarate salt in the desired polymorph. The
pharmaceutical salt 1f was isolated by filtration, the only
isolation throughout the entire total synthesis. The telescoped
synthesis afforded 33.5 kg of API with 99% purity in 54%
overall yield from 31.5 kg of 3 in our plant.
−10 °C. A solution of citric acid (100 g) in water (400 mL) was
added, and the mixture was warmed to 25 °C. Acetonitrile was
distilled off at 25 °C under reduced pressure. To the residue,
ethyl acetate (800 mL) and water (400 mL) were added. The
organic layer was separated, washed with water (600 mL), 10%
(w/w) aqueous NaHCO3 solution (600 mL), 10% (w/w)
aqueous NaCl solution (600 mL), and concentrated at 25 °C
under reduced pressure until a final volume of ∼160 mL was
reached. Acetonitrile was added to the residue until a final
weight of 900 g (∼950 mL) was reached to obtain 4 (91.4 g,
198 mmol, 100% yield as is) as a solution, which was used for
the next step without further purification. HPLC for 4 (tR =
8.32 min, identical to authentic sample) 98.4% purity; 2 (tR =
3.92 min): Agilent SB-C18 150 × 3 mm, flow rate = 1 mL/min,
40 °C, gradient elution from 10:90 A−B to 90:10 A−B over 15
min; A = acetonitrile; B = 0.1% TFA in water; UV λ = 254 nm.
(3R,4S,5S)-1-(tert-Butoxycarbonyl)-5-(cyclopropyl(5-
isopropylpyridin-2-yl)carbamoyl)-4-hydroxypiperidine-
3-carboxylic acid (5, Laboratory Scale Process). To the
acetonitrile solution of 4 (900 g, containing 91.4 g of 4, 198
mmol as is) were added water (20 mL, 1.1 mol), lithium
bromide (172 g, 1.98 mol), and triethylamine (100 g, 990
mmol) at 20 °C. The mixture was stirred at 20 °C for 6 h.
Water (800 mL) was added, and the mixture was concentrated
at 20 °C under reduced pressure until all acetonitrile was
collected. The remaining aqueous solution was washed with
tert-butyl methyl ether (2 × 400 mL) and adjusted to pH 2 with
15% (w/w) aqueous KHSO4 solution. Product was extracted
with isopropyl acetate (2 × 600 mL). The combined organic
layer was washed with water (600 mL), 10% (w/w) aqueous
NaCl solution (600 mL), and concentrated at 25 °C under
reduced pressure until a final volume of ∼950 mL (∼900 g)
was reached to afford 5 (88.6 g, 198 mmol, 100% yield as is) as
a solution in isopropyl acetate, which was used for the next step
without further purification. HPLC for 5 (tR = 7.15 min,
identical to authentic sample) 99% purity; 4 (tR = 8.32 min):
Agilent SB-C18 150 × 3 mm, flow rate = 1 mL/min, 40 °C,
gradient elution from 10:90 A−B to 90:10 A−B over 15 min; A
= acetonitrile; B = 0.1% TFA in water; UV λ = 254 nm.
(3S,4R,5R)-tert-Butyl-3-(cyclopropyl-(5-isopropylpyri-
din-2-yl)carbamoyl)-5-((R)-1-ethoxy-4-methylpentan-2-
ylcarbamoyl)-4-hydroxypiperidine-1-carboxylate (7,
Laboratory Scale Process). To the isopropyl acetate solution
of 5 (900 g, containing 88.6 g of 5, 198 mmol as is) at 0 °C was
added water (20 mL), HOBt (5.34 g, 39.6 mmol; CAUTION:
dry HOBt can be explosive), 6 (43.2 g, 238 mmol), N-
methylmorpholine (24 g, 238 mmol), and EDC (45.6 g, 238
mmol). The mixture was warmed to 25 °C and stirred for 6 h.
Water (600 mL) was charged. The organic layer was separated
and washed with 10% (w/w) aqueous NaHCO3 solution (600
mL), 10% (w/w) aqueous citric acid solution (600 mL), and
10% (w/w) aqueous NaCl solution (600 mL). The organic
solution was concentrated at 25 °C under reduced pressure
until a final volume of ∼600 mL (∼600 g) was reached to
furnish 7 (113.7 g, 198 mmol, 100% yield as is) as a solution in
isopropyl acetate, which was used for the next step without
further purification. HPLC for 7 (tR = 10.0 min, identical to
authentic sample), 99.4% purity; 5 (tR = 7.15 min): Agilent SB-
C18 150 × 3 mm, flow rate = 1 mL/min, 40 °C, gradient
elution from 10:90 A−B to 90:10 A−B over 15 min; A =
acetonitrile; B = 0.1% TFA in water; UV λ = 254 nm.
CONCLUSIONS
■
A telescoped process was developed for the manufacturing of 1f
via a five-step synthetic route without isolating any
intermediates (Scheme 9). Guided by plausible reaction
mechanisms we proposed, optimization of each individual
reaction step was accomplished by minimizing impurity
profiles. The goal of developing a total telescoped and scalable
synthesis was achieved. Highlights of this scalable synthesis
include: (1) the byproduct-controlled amidation protocol using
Ghosez’s reagent in the presence of a mild acid scavenger for
the formation of the first sterically hindered amide bond; (2)
the chemoselective hydrolysis of a sterically hindered ester; (3)
an efficient amidation reaction employing a soluble carbodii-
mide leading to the second sterically hindered amide bond; (4)
filtration of the fumarate salt of the final drug substance, being
the only necessary isolation step throughout the total synthesis.
Without the necessity of isolating any intermediates, this
telescoped process conserved equipment usage, consumed less
solvents, and minimized process waste generation, energy
consumption, personnel exposure, and environmental impact.
Additionally, telescoping of the steps achieved “unit operation
economy” as it avoided necessary operations required for
reactor cleanings compared to if intermediates had been
isolated, which traditionally utilizes solvents, water, detergents,
and energy (for refluxing, distilling, etc.). We propose to
include these cleaning solvents and materials into the process
mass intensity calculation10 to reflect the reality.11 In
conclusion, this telescoped synthesis furnished kilogram
quantities of high-quality active pharmaceutical ingredient.
EXPERIMENTAL SECTION
■
General. Starting materials 21 and 312 were purchased form
CiVentiChem and Archimica Chemicals, respectively. Com-
pound 61 was purchased from Richmond Chemical Corpo-
ration. Reverse-phase HPLC analyses were performed on an
Agilent HPLC system with a DAD detector (area normal-
ization).
(3R,4S,5S)-1-tert-Butyl-3-methyl-b-cyclopropyl(5-iso-
propylpyridin-2-yl)carbamoyl-4-hydroxypiperidine-1,3-
dicarboxylate (4, Laboratory Scale Process). To a solution
of 3 (60.0 g, 198 mmol) in acetonitrile (800 mL) was added 1-
chloro-N,N-2-trimethyl-1-propenylamine (32.6 g, 238 mmol)
over 20 min at 0 °C. The suspension was stirred at 0 °C for 1 h
to obtain a clear solution. The resulting solution was cooled to
−10 °C and charged to a solution of 2 (42.0 g, 238 mmol), 2-
(dimethylamino)pyridine (36.4 g, 298 mmol), and acetonitrile
(600 mL) at −10 °C. The mixture was stirred for 30 min at
(3S,4R,5R)-N3-Cyclopropyl-N5-((R)-1-ethoxy-4-meth-
ylpentan-2-yl)-4-hydroxy-N3-(5-isopropylpyridin-2-yl)-
E
dx.doi.org/10.1021/op500116w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
piperidine-3,5-dicarboxamide (1, Laboratory Scale Proc-
ess). To the isopropyl acetate solution of 7 (600 g, containing
113.7 g of 7, 198 mmol as is) at 0 °C was added 6 N aqueous
HCl solution (496 g). The mixture was stirred at 0 °C for 5 h.
Isopropyl acetate (500 mL), 50% (w/w) aqueous NaOH
solution (246 g), and NaCl (40 g) were added in sequence at 0
°C. The organic layer was separated and saved. The aqueous
layer was extracted with isopropyl acetate (600 mL). The
combined organic layer was washed with saturated NaCl
solution (600 mL), filtered over a pad of Celite, and
concentrated at 25 °C under reduced pressure until a final
volume of ∼120 mL was reached. Ethyl acetate (600 mL) was
added, filtered over a pad of Celite, and concentrated at 25 °C
under reduced pressure until a final volume of ∼120 mL was
reached. The remaining solution was diluted with ethyl acetate
(200 mL) to obtain 1 (94 g, 198 mmol as is) as a solution (300
g) in ethyl acetate, which was used for the next step without
further purification. HPLC for 1 (tR = 6.2 min, identical to
authentic sample), 98.5% purity; 7 (tR = 10.0 min): Agilent SB-
C18 150 × 3 mm, flow rate = 1 mL/min, 40 °C, gradient
elution from 10:90 A−B to 90:10 A−B over 15 min; A =
acetonitrile; B = 0.1% TFA in water; UV λ = 254 nm.
(3S,4R,5R)-N3-Cyclopropyl-N5-((R)-1-ethoxy-4-meth-
ylpentan-2-yl)-4-hydroxy-N3-(5-isopropylpyridin-2-yl)-
piperidine-3,5-dicarboxamide, Monofumarate Salt (1f,
Laboratory Scale Process). To a solution of fumaric acid
(11.5 g, 99 mmol), ethanol (115 mL), and ethyl acetate (230
mL) at 40 °C was added the ethyl acetate solution of 1 (150 g,
containing 47 g of 1, 99 mmol). The solution was filtered over a
pad of Celite and diluted with ethyl acetate (520 mL) at 40 °C.
To the clear solution, seeds was added and stirred at 40 °C for
1 h. The mixture was cooled to 25 °C over 1 h. Ethyl acetate
(200 mL) was added and stirred for 16 h. The precipitate was
filtered, washed with a mixture of ethanol and ethyl acetate (1:9
v/v, 2 × 100 mL), and dried under reduced pressure at 40 °C
for 16 h to afford 1f (25.2 g, 42.7 mmol, 43% overall yield from
2) as an off-white solid: mp 207−213 °C; 1H NMR (500 MHz,
DMSO-d6); 8.35 (d, J = 1.3 Hz, 1H), 7.75 (dd, J = 7.8, 1.3 Hz,
1 H), 7.62 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.47 (s,
2H), 4.37 (br s, 1H), 3.92 (m, 1H), 3.42 (m, 2H), 3.30 (m,
1H), 3.20−3.10 (m, 2H), 3.10−2.95 (m, 5H), 1.57 (m, 1H),
1.30 (m, 2H), 1.24 (d, J = 8.3 Hz, 6H), 1.08 (t, J = 6.5 Hz, 3H),
0.87 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H), 0.80 (m, 2
H), 0.55 (m, 1H), 0.45 (m, 1H); 13C NMR (CDCl3, 75 MHz)
172.6, 169.6, 167.8, 152.4, 146.8, 141.8, 135.8, 135.0, 121.7,
72.4, 65.5, 64.2, 46.2, 44.4, 42.7, 30.5, 29.9, 24.2, 23.4, 21.8,
15.0, 8.8; MS (ESI) m/z 475.1 (M + H+); HPLC for 1 (tR = 6.2
min), purity 99.0%: Agilent SB-C18 150 × 3 mm, flow rate = 1
mL/min, 40 °C, gradient elution from 10:90 A−B to 90:10 A−
B over 15 min; A = acetonitrile; B = 0.1% TFA in water; UV λ
= 254 nm.
Michael Girgis, Lech Ciszewski, Melissa Lin, and Lichun Shen
for many helpful discussions.
REFERENCES
■
(1) (a) Yokokawa, F.; Ehara, T.; Kawakami, S.; Irie, O.; Suzuki, M.;
Hiyomi, Y.; Toyao, T. U.S. Patent Application Publication, 2008/
0319018, Dec 25, 2008. (b) Ehara, T.; Irie, O.; Kosaka, T.; Kanazawa,
T.; Breitenstein, W.; Grosche, P.; Ostermann, N.; Suzuki, M.;
Kawakami, S.; Konishi, K.; Hitomi, Y.; Toyao, A.; Gunji, H.; Cumin,
F.; Schiering, N.; Wagner, T.; Rigel, D. F.; Webb, R. L.; Maibaum, J.;
Yokokawa, F. ACS Med. Chem. Lett. 2014, No. 10.1021/ml500137b.
(2) (a) Shieh, W.-C.; Chen, Z.; Xue, S.; McKenna, J.; Wang, R.-M.;
̌
Prasad, K.; Repic, O. Tetrahedron Lett. 2008, 49, 5359−5362.
(b) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron
Lett. 1989, 30, 1927−1930. (c) Jou, G.; Gonzalez, I.; Albericio, F.;
Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 1997, 62, 354−366. (d) Xu,
J. C.; Li, P. Tetrahedron Lett. 1999, 40, 8301−8304. (e) Xu, J. C.; Li, P.
Tetrahedron 2000, 56, 9949−9955.
(3) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.;
Ghosez, L. J. Chem. Soc., Chem. Commun. 1979, 1180−1181.
(4) Kennedy, L. J. Tetrahedron Lett. 2010, 51, 2010−2013.
(5) Conversion of cyclohexanols to cyclohexenes (4−82%) by
Ghosez’s reagent was reported, see: Munyemana, F.; Frisque-Hesbain,
A.-M.; Devos, A.; Ghosez, L. Tetrahedron Lett. 1989, 30, 3077−3080.
(6) The pKa data was acquired by conducting SciFinder search, which
revealed the calculated value using Advanced Chemistry Development
(ACD/Laboratories) Software.
(7) Mattsson, S.; Dahlstrom, M.; Karlsson, S. Tetrahedron Lett. 2007,
̈
48, 2497−2499.
(8) For a recent review on applications of EDC in organic synthesis,
see: Goyal, N. Synlett 2010, 2, 335−336.
(9) Liu, Y.; Prashad, M.; Shieh, W.-C. Org. Process Res. Dev. 2014, 18,
239−245.
(10) Jimen
Manley, J. B. Org. Process Res. Dev. 2011, 15, 912−917.
(11) Jimenez-Gonzalez, C.; Constable, D. J. C.; Ponder, C. S. Chem.
́ ́
ez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.;
́
́
Soc. Rev. 2012, 41, 1485−1498.
(12) Liang, X.; Lohse, A.; Bols, M. J. Org. Chem. 2000, 65, 7432−
7437.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wen-chung.shieh@novartis.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Mrs. Jyoti Patel and Lingfen Rao, Mr.
Kevin Vargas, Mr. Terence Lo, as well as Drs. Edwin Villhauer,
F
dx.doi.org/10.1021/op500116w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX