Synthesis and cross coupling of a highly substituted 2-pyridylboronate: Application to the large scale synthesis of a mineralocorticoid antagonist

Article abstract of DOI:10.1016/j.tetlet.2011.10.052

The large scale synthesis of functionalized 2-pyridylboronate 8 and optimization of its Suzuki-Miyaura coupling to chloropyrazoline (R)-7 to provide a scalable synthesis of mineralocorticoid antagonist (R)-1 is described.

Full text of DOI:10.1016/j.tetlet.2011.10.052

Tetrahedron Letters 52 (2011) 7025–7029
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and cross coupling of a highly substituted 2-pyridylboronate:
application to the large scale synthesis of a mineralocorticoid antagonist
Charles Boos, Daniel M. Bowles, Cuiman Cai, Agustin Casimiro-Garcia, Xiangyang Chen,
⇑
Catherine A. Hulford, Sandra M. Jennings, E. Jason Kiser, David W. Piotrowski ,
Matthew Sammons, Robert A. Wade
Pfizer Global Research & Development, Groton/New London Laboratories, Pfizer Inc., Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The large scale synthesis of a functionalized 2-pyridylboronate 8 and optimization of its Suzuki–Miyaura
coupling to chloropyrazoline (R)-7 to provide a scalable synthesis of mineralocorticoid antagonist (R)-1 is
described.
Received 15 September 2011
Revised 8 October 2011
Accepted 10 October 2011
Available online 23 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Suzuki–Miyaura coupling
2-Pyridylboronate
Pyrazoline
Large-scale synthesis
The abnormal activation of the mineralocorticoid receptor (MR)
by elevated levels of the endogenous agonist aldosterone leads to
salt imbalance causing hypertension and other detrimental effects
to the cardiovascular system such as glomerular and tubular scle-
rosis. Selective steroidal MR antagonists, spironolactone and epl-
erenone, are marketed agents for lowering blood pressure in
hypertensive patients. However, these steroidal compounds are
contraindicated in diabetic patients. As part of a program to dis-
cover nonsteroidal MR antagonists that offer the potential to treat
hypertension and diabetic nephropathy, compounds from the pyr-
azoline chemotype emerged as promising candidates. Compound
(R)-1 was identified as a potential follow-on to clinical candidate
PF-03882845 (Fig. 1).1 In order to support preclinical toxicology
studies, bulk quantities of (R)-1 were required. Herein, we describe
the synthesis of a 2-pyridylboronate and optimization of its
coupling to a chloropyrazoline to provide a scalable synthesis of
(R)-1.
scale). Subsequent Knoevenagel condensation of 3 and cyclopen-
tanecarboxaldehyde in the presence of pyrrolidine provided
a,b-unsaturated ketone 5 in 60% yield after chromatography. Con-
densation of 5 with aryl hydrazine 6 in the presence of sodium eth-
oxide in ethanol followed by ester hydrolysis provided rac-1 in
78% yield. Compound (R)-1 could be obtained in an enantiopure
form by chiral HPLC separation (Scheme 1).3
In examination of this route for suitability for scale up, several
drawbacks were uncovered. First, the route is linear and several
steps require purification by chromatography. Second, the dime-
thylation of 2 to provide 3 either required the use of the expensive
Ag2CO3 reagent to obtain reasonable conversion or required chro-
matography followed by recrystallization to remove the ethyl ke-
tone by-product 4 formed under the Cs2CO3/DMF conditions.
Lastly, the late stage chromatographic separation of enantiomers
proved to be undesirable because of the low solubility4 of rac-1
and disposal of more than half of the final product.
The original route to (R)-1, depicted in Scheme 1, was suitable
for delivering milligram quantities for testing. The sequence began
A more convergent route was devised based on the retro-
synthetic disconnection depicted in Figure 2. The seemingly
obvious bond connection via Suzuki–Miyaura coupling between
2-pyridylboronate (R)-7 and 3-chloropyrazoline 8 was not without
challenges. While scalable chemistry was in place for the required
3-chloropyrazoline 7,5 chloropyrazolines are uncommon coupling
partners. Prior to the recent report from Pfizer labs,1 the only
known Suzuki–Miyaura couplings of cyclic imidoyl chlorides6 or
sulfonates7 with aryl boronic acids or aryl trifluoroborates had
been performed on milligram scale and most effectively under
with 6-acetyl-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid
2
which was obtained from 3,3-dimethoxy-2-butanone using a
known multi-gram route.2 Conversion of the hydroxy acid 2 into
methoxy ester 3 could be effected by treatment with methyl iodide
and Ag2CO3 in CHCl3 (58%, 2 g scale) or Cs2CO3 in DMF (37%, 3 g
⇑
Corresponding author.
E-mail address: david.w.piotrowski@pfizer.com (D.W. Piotrowski).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.052

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C. Boos et al. / Tetrahedron Letters 52 (2011) 7025–7029
10 into the 2-methoxy derivative 11 was most effectively con-
O
O
ducted by portion-wise addition of solid sodium methoxide to a
CH2Cl2 solution of 10 (94% yield). Use of other solvents or of a
methoxide solution eroded regioselectivity leading to a lower
isolated yield of 11 that was contaminated with the undesired
6-methoxy and 2,6-dimethoxy by-products.12 Boronate 8 was syn-
thesized under standard conditions13 using bis(pinacolato)dibo-
rane, KOAc and PdCl2(dppf) in DME to afford a 74% yield after
recrystallization from heptanes (Scheme 2). Compound 8 was ob-
served to degrade slowly at room temperature, but could be stored
in the refrigerator with no noticeable decomposition over several
months. The route described above, with minor modifications,
was robust and scalable to provide hundred gram quantities of 8.5
We were pleased to find that coupling between rac-7 and 8
catalyzed by 5% Pd(PPh3)4 under standard Suzuki–Miyaura condi-
tions14 provided ester rac-12 in 56% yield after chromatography
(Scheme 3). Analysis of the crude reaction mixture by HPLC
revealed ca. 20% of a homocoupled dimer 13 as the major
impurity.15 The racemic ester 12 could be converted into acid
(R)-1 on multi-gram scale by subjection to chiral SFC chromatogra-
phy followed by hydrolysis and crystallization. However, the poor
solubility of the ester 12 or acid 1 substrates made chromatogra-
phy a laborious process. It was clear that the final sequence could
be improved by finding conditions that minimized formation of the
by-product and by separation of enantiomers at a stage that
utilized a more soluble substrate.
O
O
O
H
O
H
H
SAc
H
H
O
O
CO2Me
spironolactone
eplerenone
O
N
N
N
N
OH
N
OH
O
NC
NC
(R)-1
MR IC50 = 4.2 nM
PF-03882845
Cl
MR IC50 = 9 nM
Figure 1. Steroidal and nonsteroidal MR antagonists.
microwave conditions. As such, we expected that coupling
reactions with 3-chloropyrazolines would be nontrivial and likely
require extensive optimization. Furthermore, the boronate 8 was
unknown but was envisaged to be accessible from the
commercially available 2,6-dichloropyridine-3-carboxylic acid 9.
While coupling reactions of heterocyclic boron reagents (e.g.,
3- or 4-pyridine boronic acid) are common, coupling of 2-pyridine
variants are less common and often complicated by homo-coupling
or sensitivity to proto-deboronation. Solutions to some of these
concerns have been addressed in the context of simply substituted
2-pyridine boron reagents8 by the use of solid support9 or
specialized catalyst systems.10 Many of the pitfalls associated with
the coupling of 2-pyridine reagents are highlighted in a recent
review.11
Homocoupled side products from Suzuki–Miyaura couplings
can often be suppressed by using an alternative phosphine ligand,
base or solvent. Parallel optimization of the conditions for the
Suzuki–Miyaura coupling was undertaken using Chemspeed
SWING platform to first examine a range of ligands and bases in
aqueous THF (Tables 1 and 2), followed by assessment of alterna-
tive solvent systems. In the first screen, catalysts examined
included bis(triphenylphosphine)palladium (II) chloride (6 mol %)
and tris(dibenzylideneacetone) dipalladium (0) (3 mol %) with a
The preparation of 8 commenced with esterification of carbox-
ylic acid 9 under classical conditions to provide ester 10 in 75%
yield after recrystallization from heptane. Selective conversion of
O
O
O
O
O
O
O
O
OH
O
O
O
c
a or b
+
N
H
N
N
N
O
O
O
O
2
3
5
4
NC
O
O
N
N
NHNH2
N
N
1. d,
2. e
N
N
f
6
OH
OH
NC
O
NC
O
rac-1
(R)-1
Scheme 1. Original synthesis of (R)-1. Reaction Conditions: (a) MeI, Ag2CO3, CHCl3, 58%; (b) MeI, Cs2CO3, DMF, 37%; (c) cyclopentanecarboxaldehyde, pyrrolidine, MeOH, 60%;
(d) 6, NaOEt, EtOH, 50 °C; (e) aq HCl, 78% (two steps) and (f) chiral SFC chromatography.
O
O
OH
O
Cl
N
N
+
N
N
N
O
B
N
O
O
O
NC
NC
(R)-1
(R)-7
8
Figure 2. Retrosynthesis of (R)-1.

C. Boos et al. / Tetrahedron Letters 52 (2011) 7025–7029
7027
O
O
O
O
O
O
O
c
OH
b
O
a
O
B
O
N
Cl
N
Cl
Cl
N
Cl
Cl
N
O
8
9
10
11
Scheme 2. Preparation of 2-pyridylboronate 8. Conditions: (a) MeOH, SOCl2, 75%; (b) solid NaOMe, CH2Cl2, 94% and (c) bis(pinacolato)diborane, PdCl2(dppf), KOAc, DME, 74%.
O
O
O
O
O
O
a
O
Cl
N
N
+
N
O
N
N
OR
N
N
B
O
N
O
O
O
O
NC
NC
rac-7
8
R = Me 12
R = H (R)-
13
b, c
1
Scheme 3. Initial Suzuki–Miyaura coupling of rac-7. Conditions: (a) 5% Pd(PPh3)4, 2 M Na2CO3, DME, 80 °C, 56%; (b) chiral SFC chromatography (column: AD–H, 21 ꢁ 250,
mobile phase: 65/35 carbon dioxide/methanol, 65 mL/min) and (c) LiOH, aq THF.
Table 1
Different Pd-catalyst/ligands in the presence of K2CO3
Ligand
Normalized HPLC area under the curve
By-product 13
rac-7
8
rac-12
Othera
Pd2(dba)3/Josiphos
Pd2(dba)3/Tri-o-tolylphosphine
Pd2(dba)3/S-Phos
Pd2(dba)3/Ru-Phos
Pd2(dba)3/X-Phos
36
27
14
28
5
1
2
0
0
0
0
14
2
2
3
2
15
3
40
43
76
59
34
66
44
26
17
29
(Ph3P)2PdCl2
4
8
a
Area of all other peaks combined.
Table 2
With optimized coupling conditions in hand, the coupling
partner (R)-7 was prepared. Indeed, chloropyrazoline rac-7
proved to be a more soluble substrate than 1 thereby allowing
for a more practical separation of enantiomers17 on kilogram
scale (over 500 g of (R)-7 was obtained with ee >97%). Suzuki–
Miyaura coupling provided (R)-12 along with ꢀ2% of the homo-
coupled by-product 13 (Scheme 4). On scale, by-product 13 was
found to be very difficult to remove with either chromatography
or crystallization. Therefore, (R)-1 was isolated and purified via
MTBE-heptane slurry (product purities by HPLC >96%, ee >99%).
The homocoupled by-product was the major HPLC impurity at
levels of 1.3–2.5%. Simultaneous hydrolysis of the product and
by-product esters was conducted with 1 N aq NaOH in THF at
40 °C. The crude product was taken up in CH2Cl2 and filtered
through diatomaceous earth in order to remove the insoluble dia-
cid impurity 14. A stable crystal form of (R)-1 was obtained by
heating a crude slurry in ethanol-water at 80 °C. The final product
(R)-1 was isolated by filtration in 95% yield with >99.9% purity
(achiral and chiral HPLC).
As a result of the optimization work described herein, the
original chemistry route was transformed into a route capable of
preparing hundreds of grams of (R)-1 in a single campaign. The
original linear route that required late-stage separation of enanti-
omers was replaced with a more convergent route utilizing a key
Suzuki–Miyaura coupling between 3-chloropyrazoline (R)-7 and
the highly substituted boronate 8. The advantages of the latter
route include (1) separation of more soluble rac-7 by chiral chro-
matography at an earlier stage, (2) refinement of Suzuki–Miyaura
coupling to minimize by-product formation and (3) removal of
purification by chromatography by enabling purity upgrade during
crystallization of a stable polymorph of (R)-1.
Different bases in the presence of Pd2(dba)3/X-Phos
Base
Normalized HPLC area under the curve
rac-7
8
By-product 13
rac-12
Othera
Ba(OH)2
LiOH
K2CO3
Cs2CO3
CsF
KF
Na3PO4
Li2CO3
20
8
6
12
14
27
13
3
0
0
0
0
2
5
0
0
0
0
2
2
8
10
2
2
0
0
80
92
16
36
25
25
21
35
76
50
51
33
64
60
a
Area of all other peaks combined.
number of different ligands (X-Phos, S-Phos, Ru-Phos, JosiPhos and
tri-o-tolylphosphine). Bases assessed included K2CO3, LiOH,
Ba(OH)2, Li2CO3, Na3PO4, CsF, KF, Cs2CO3 , and HCO2K. The reactions
were monitored by HPLC for starting materials rac-7 and 8, by-
product 13 and conversion to product rac-12 for the different re-
agent combinations. Overall, we observed that triphenylphosphine
almost uniformly produced the most homocoupled by-product and
tri-o-tolylphosphine generally led to poor conversion. X-Phos, on
the other hand, best balanced high conversion with minimized
homocoupled by-product. Cesium or potassium carbonate and tri-
sodium phosphate were among the best bases for overall conver-
sion to product. A secondary screen compared the best bases
(Cs2CO3, K2CO3, and Na3PO4) paired with Pd2(dba)3/X-Phos in
alternative solvents (EtOH or n-BuOH, aqueous or anhydrous).
Alcoholic solvents offered no particular advantage. Thus, thorough
catalyst screening allowed for identification of the best coupling
conditions, that is Pd2(dba)3/X-Phos with 1 M K2CO3 in THF at
65 °C.16

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C. Boos et al. / Tetrahedron Letters 52 (2011) 7025–7029
O
O
O
a
O
Cl
+
N
N
O
N
N
N
B
O
N
O
O
(R)-7
8
(R)-12
NC
NC
O
O
O
b, c
+
N
N
N
OH
RO
N
N
OR
O
O
O
NC
(
R
)-1
13
R = Me
R = H 14
Scheme 4. Scale-up of (R)-1. Conditions: (a) Pd2(dba)3, X-Phos, 1 M K2CO3, THF, 65 °C, 85%; (b) 1 N NaOH, THF, 40 °C and (c) EtOH/H2O slurry, 95% (two steps).
at 40 °C for 5.5 h, the mixture was cooled and the pH was adjusted
to pH 3 with 1 N aq HCl (1.2 L). Ethyl acetate (3.0 L) was added and
the mixture was phase separated. The organic layer was washed
with half-saturated brine (1.0 L), filtered through Celite, and con-
centrated. The thick paste was taken up in CH2Cl2 (2.0 L), dried
over MgSO4, filtered through Celite, concentrated, and dried under
vacuum. The amorphous solid was crystallized from 1:1 ethanol/
water (4.2 L, heated for 2 h at 80 °C), cooled, filtered, and dried un-
der vacuum to yield (R)-1 (364 g, 95%) as a crystalline solid. mp
179–181 °C. HPLC (purity) 99.5%. 1H NMR (500 MHz, DMSO-d6) d
12.94 (1H, b s), 8.11 (1H, d, J = 8.2 Hz), 7.66 (1H, d, J = 8.2 Hz),
7.56 (1H, d, J = 8.2 Hz), 7.22 (1H, d, J = 1.9 Hz), 7.10 (1H, dd,
J = 8.6, 2.2 Hz), 4.87 (1H, dt, J = 11.7, 4.0 Hz), 3.94 (3H, s), 3.45
(1H, dd, J = 18.7, 11.9 Hz), 3.19 (1H, dd, J = 18.7, 4.3 Hz), 2.41 (3H,
s), 1.79–1–69 (1H, m), 1.63–1.17 (7H, m), 1.08–0.95 (1H, m). MS
(AP) m/z 405.2 (M+H)+. Anal. Calcd for C23H24N4O3: C, 68.30; H,
5.98; N, 13.85. Found: C, 68.31; H, 6.05; N, 13.81.
Representative experimental procedures
Preparation of methyl 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)nicotinate 8
A mixture of methyl 6-chloro-2-methoxynicotinate 11 (94.0 g,
0.47 mol), bis(pinacolato) diboron (130.0 g, 0.51 mol), potassium
acetate (137.0 g, 1.4 mol), and 1,2-dimethoxyethane (705 mL)
was sparged for 30 min with rapid nitrogen bubbling. [1,10-
bis(diphenylphosphino)ferrocene] palladium (II) chloride (19.0 g,
23.3 mmol) was added and the mixture was heated under reflux.
After 12 h, the mixture was diluted with ethyl acetate (150 mL)
and concentrated to dryness. The residue was taken up in ethyl
acetate (750 mL), aqueous saturated sodium bicarbonate
(300 mL), and water (200 mL). The organic layer was washed with
water (500 mL) and concentrated to dryness. The residue was
taken up in 500 mL hot heptane (78 °C), hot filtered through Celite
and cooled with stirring. The resulting slurry was filtered and dried
to yield boronate 8 (95 g, 70%) as a tan solid. Another campaign
under similar conditions afforded 242.0 g (73.6%) of boronate 8
as an off-white solid. GC purity 98%. 1H NMR (400 MHz, DMSO-
d6) d 8.02 (1H, d, J = 7.2 Hz), 7.42 (1H, d, J = 7.3 Hz), 3.90 (3H, s),
3.78 (3H, s), 1.28 (12H, s).
Acknowledgments
We thank Laurence Philippe, Bob Depianta and Tony Yan for
separation of rac-1 and -12, Jeff Hitchcock for large scale prepara-
tion of rac-7, Charles Grill, Ming Zeng, Steven Zelinsky, Bob
Pearson, Paul Simonds for the separation of rac-7, Brian Samas
for the X-ray crystal structure of (R)-7 and Dr. Vincent Mascitti
and Javier Magano for proofreading the manuscript.
Suzuki–Miyaura coupling of (R)-7 and 8 to provide ester (R)-12
(R)-3-Chloropyrazoline 7 (116.6 g, 405.0 mmol) and 2-pyridyl-
boronate 8 (132.1 g, 450.6 mmol) were combined in THF (1.0 L)
and 1 M aq K2CO3 (1.0 L) and the mixture was sparged with
nitrogen for 1 h. Tris(dibenzylideneacetone)dipalladium-chloro-
form adduct (3.53 g, 3.4 mmol) and X-Phos (6.5 g, 13.3 mmol) were
added and the mixture was heated at 60 °C for 4 h. The reaction
was cooled to room temperature, charged with ethyl acetate
(500 mL) and filtered through Celite. The Celite was washed with
2 ꢁ 250 mL ethyl acetate. The combined organic layers were
washed sequentially with water (250 mL) and brine (250 mL),
and then concentrated. The residue was taken up in methyl t-butyl
ether (850 mL) and heptane (850 mL). After stirring at room
temperature for 3 h, the resulting slurry was filtered. The collected
solids were rinsed with 50% methyl t-butyl ether in heptane
(500 mL) and dried under vacuum at 35 °C to give ester (R)-12
(143.9 g, 85%) as a yellow solid with HPLC purity 98.1% (1.4% of
by-product 13) that was carried forward crude.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.052.
References and notes
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