Synthesis of spiropiperidine lactam acetyl-CoA carboxylase inhibitors

Article abstract of DOI:10.1021/jo3014808

The synthesis of 4′,6′-dihydrospiro[piperidine-4,5′- pyrazolo[3,4-c]pyridin]-7′(2′H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.

Full text of DOI:10.1021/jo3014808

Article
pubs.acs.org/joc
Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase
Inhibitors
Kim Huard,† Scott W. Bagley,† Elnaz Menhaji-Klotz,*,† Cathy Preville,† James A. Southers, Jr.,†
́
Aaron C. Smith,† David J. Edmonds,† John C. Lucas,† Matthew F. Dunn,† Nigel M. Allanson,‡
Emma L. Blaney,‡ Carmen N. Garcia-Irizarry,† Jeffrey T. Kohrt,† David A. Griffith,† and Robert L. Dow†
†Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States
‡Peakdale Molecular Ltd, Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak, SK23 0PG, United Kingdom
S
* Supporting Information
ABSTRACT: The synthesis of 4′,6′-dihydrospiro[piperidine-
4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one-based acetyl-CoA
carboxylase inhibitors is reported. The hitherto unknown N-
2 tert-butyl pyrazolospirolactam core was synthesized from
ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-
step synthesis requiring only one chromatography procedure.
The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates.
Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under
both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type
cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl
lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of
potent analogues.
INTRODUCTION
■
Type 2 diabetes mellitus (T2DM) is associated with a
fundamental imbalance in lipid metabolism, and these
alterations are hypothesized to contribute to the molecular
pathogenesis of insulin resistance. Fatty acid oxidation is
suppressed, and the rate of hepatic de novo lipogenesis is
increased in the insulin-resistant state.1 Acetyl-CoA carboxylase
(ACC) serves as a critical switch, regulating the transition from
lipogenic to oxidative lipid metabolism. Inhibition of ACC
activity is expected to have a favorable impact on both skeletal
muscle and hepatic insulin sensitivity by rebalancing the
alterations in lipid metabolism associated with the pathogenesis
of insulin resistance. Consequently, pharmacologic ACC
inhibitors may have utility in the treatment of T2DM.2
Pyrazole spiropyranone 1 was recently reported by Pfizer as a
potent ACC inhibitor.3 A chemical stability issue involving
base-mediated retro-Michael-type ring-opening reaction and
subsequent olefin migration was addressed with carbocyclic
variant 2.4,5 To explore alternative SAR, we sought to replace
the ketone in compound 2 with a lactam core as exemplified by
compound 3.6
Described here is the route that provided the desired N-2
tert-butyl pyrazolo-lactam scaffold (40) related to 3. This
regioselective, robust, and scalable sequence provided the
desired pyrazole spirolactam in 27% overall yield and only one
chromatography step. Synthesis of the isomeric N-1 isopropyl
series is also illustrated. This synthesis provided access to
analogues and enabled investigation of the in vitro activity for
this class of compounds. Compounds derived from the
Figure 1. Examples of Pfizer ACC inhibitors.
spirolactam core structures are currently being investigated
for the treatment of T2DM.
RETROSYNTHETIC ANALYSIS
■
A search for existing literature around the pyrazolo spirolactam
scaffold did not provide any precedents, and we were dismayed
to find only limited examples of spiro-fused dihydroisoquino-
lones such as compounds 6, 9, 11, 13, and 16 (Scheme 1). Two
examples (transformations a and b in Scheme 1) demonstrated
nucleophilic attack of a benzylic carbon upon a ketimine
derived from cyclohexanone or piperidinone, respectively, with
subsequent ring closure.7,8 Both of these examples would
require lactam N-deprotection. Additional examples made use
Received: July 23, 2012
Published: November 5, 2012
© 2012 American Chemical Society
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working with the pyrazole scaffold. For example, disconnection
of bond a via iodolactamization11 or hydroamidation12 resulted
in no reaction. Nitrene cyclization13 of olefinic precursor 20 did
not provide the desired spirolactam. Addition of a nucleophilic
pyrazole derivative to an imine to form bond b resulted in low
conversion8 to the desired product, and addition of pyrazole 17
to aziridine14 to form bond c also proved fruitless.
Scheme 1. Synthesis of Spirocyclic Dihydroisoquinolones
The retrosynthetic strategy that provided access to the
spirolactam core is described in Scheme 3. We imagined late-
Scheme 3. Retrosynthetic Strategy
stage deprotection of lactam 23 would reveal the piperidine
nitrogen that could undergo amide coupling and serve as the
point of diversity for preparing lactam-containing ACC
inhibitors. We hoped to target pyrazolo spirolactam 23 from
isocyanate 24 via Parham-type cyclization as demonstrated by
Quin et al. in their synthesis of isoindolinones.15−17 We
imagined that a Curtius rearrangement of a carboxy ester
derivative such as 25 would install the isocyanate and establish
the tertiary alkyl nitrogen atom. The all-carbon quaternary
center could be introduced via alkylation of ester 27, with a
suitably functionalized pyrazole derivative (26).
of a Lewis or protic acid (equations c and d, respectively) to
form the desired C−C bond of 11 and 13.7,9 Equation d used a
Beckmann rearrangement to form the lactam from an
intermediate spiroindanone. This reference described a
spirolactam with a fused thiophene, the only literature example
of a heterofused spirocyclic lactam that we noted in our
research. Most recently, a literature report described radical
carboamination of aryl diazonium salts and olefins to access
spirocarbocyclic dihydroisoquinolones (equation e).10
RESULTS AND DISCUSSION
■
The primary alcohol of pyrazole 31 was envisioned to be a
suitable precursor to generate the desired alkylating agent, 26.
To access 31, the synthetic sequence began with the
commercially available ethyl 3-amino-1H-pyrazole-4-carboxy-
late 28 (Scheme 4). Sandmeyer reaction with copper(II)
Scheme 2 summarizes some of our initial attempts to
synthesize the desired spirolactam 19 in light of the limited
literature precedents and illustrates the synthetic challenge of
Scheme 2. Attempted Routes toward the Lactam Core
Scheme 4. Synthesis of Primary Alcohol 31
bromide provided bromide 29, which was used without further
purification. The crude material was alkylated with in situ
prepared isobutylene (t-BuOH in sulfuric acid18) to furnish the
tert-butyl pyrazole as a mixture of the carboxylic acid and ethyl
ester (1:5 respectively) with complete regioselectivity of
alkylation as confirmed by NOE. The mixture of carboxy
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derivatives was treated with DIBAL at low temperature to
generate alcohol 31. Purification by column chromatography
provided the desired alcohol in 46% yield, over three steps from
the commercially available amino pyrazole 28.
Bromination of alcohol 31 with PBr3, to generate a good
leaving group, proved capricious with variable yields. Instead,
iodide 32 was prepared in a two-step sequence of mesylation/
chlorination and a subsequent Finkelstein reaction with NaI
(Scheme 5). This fast and reproducible method provided an
CD3OD at 0 °C, we found a significant drop in Claisen
condensation (entry 3). When the reaction was warmed to
room temperature and quenched with CD3OD, once again
Claisen condensation produced more of the troublesome side
product (entries 4 and 5). In summary, addition of the ester to
the base at 0 °C was identified as the most efficient procedure.
Having identified conditions to minimize side-product
formation, we set out to complete the desired homologation
sequence with iodide 32 (Scheme 6). In the event, excess
Scheme 5. Initial Alkylation Conditions
Scheme 6. Synthesis of Carboxylic Acid 37
amounts of ester 33 were used to consume iodide 32. This
meant that the crude reaction mixture contained ester 33 as
well as some Claisen condensation product 35 which
necessitated a chromatography step to isolate desired product
34. We found the best way to avoid chromatographic
purification was to hydrolyze the crude mixture containing
ester 34 with sodium hydroxide in methanol. The sodium
carboxylate salt of the desired product was moderately soluble
in ethyl acetate and could be extracted from the aqueous layer.
The combined organic extracts were concentrated in vacuo to
provide a solid which was triturated with dichloromethane and
heptane to remove organic impurities. Finally, the sodium salt
was treated with aqueous 1 N HCl to isolate carboxylic acid 37
as an analytically pure and colorless solid. Acid 37 was made in
66% yield over four steps from primary alcohol 31.
active electrophile without the need for purification. Alcohol 31
was treated with MsCl to provide the chloride as an oil. After
aqueous workup, the chloride was exchanged with sodium
iodide in acetone at reflux to provide pyrazolo iodide 32 which
was used crude in the subsequent alkylation. Our initial
alkylation conditions (addition of LHMDS to 33, followed by
addition of 32) resulted in formation of the desired product 34,
albeit with large quantities of the Claisen condensation side-
product 35.
Deuterium exchange experiments were undertaken to
explore the best conditions for lithium enolate formation, and
the results are summarized in Table 1. We found that while the
Appropriately functionalized carboxylic acid 37 was used to
generate the lactam core in a two-step process (Scheme 7).
Table 1. Deuterium Quenching Experiments
Scheme 7. Elaboration of Acid 37 to ACC Inhibitor 41
temp of LHMDS
addition, °C
temp of CD3OD
quench, °C
% yield
a
b
entry conditions
35
c
1
2
3
4
5
A
A
B
B
B
−78
5
−78
5
n/a
40
10
25
30
0
0
0
23
23
23
a
Reaction conditions: (A) 1.2 equiv of LHMDS was added to a 0.12
M solution of ester (1.0 equiv) in THF. Reaction conditions: (B) A
0.5 M solution of ester (1 equiv) was added to a 0.12 M solution of
b
1
LHMDS (1.2 equiv) in THF. Determined by H NMR, relative to
c
ethyl N-Boc-piperidine-4-carboxylate. No enolate formation.
desired enolate was not formed at −78 °C (entry 1), the
Claisen condensation side product formed to a greater extent as
the reaction temperature was raised. For example, adding base
to a solution of 33 at 5 °C and quenching with CD3OD at 5 °C
resulted in significant formation of 35 (entry 2). When the
order of addition was reversed, i.e., a solution of the ester was
added to a solution of the LHMDS at 0 °C and quenched with
First, compound 37 was treated with DPPA and Et3N to effect
a Curtius rearrangement and install the tertiary alkyl amine
functionality, in the form of isocyanate 38, in 91% yield. While
we found that the isocyanate was stable enough to survive
column chromatography, it was isolated from the crude
reaction mixture as a gum and used without further purification.
Because of safety concerns associated with running large-scale
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Curtius reactions, conditions were developed for this trans-
formation in a flow reactor.19 ISCO pumps were used to
combine a toluene solution of acid 37 and Et3N with a toluene
solution of diphenylphosphoryl azide within a flow reactor. The
reactor residence time was approximately 90 min, and the loop
was maintained at 120 °C and 500 psi. As with the conventional
heating conditions, aqueous workup of the flow eluent provided
crude material that was used without further purification.
Cyclization of isocyanate 38 was investigated under a range
of conditions (Table 2). Reaction of 38 with either sec-
This is exemplified by product 41 which proved to be a potent
ACC inhibitor with an IC50 value of 67 nM.21
The favorable properties of the N-2 tert-butyl pyrazole
lactams generated interest in the related N-1 isopropyl
analogues. Scheme 8 describes the synthesis of a representative
N-1 pyrazole analogue using the same key bond disconnections
to form the spirolactam. Commercially available ethyl (ethoxy-
methylene) cyanoacetate was converted to N-1 pyrazole 44 in
two steps via regioselective condensation using isopropylhy-
drazine22 followed by a subsequent Sandmeyer reaction. With
the isopropyl group appropriately installed at N-1, ethyl ester
44 was then converted to the desired isopropyl lactam 48 in a
similar synthetic sequence as discussed above for the N-2 tert-
butyl series.23 The isopropyl lactam was acylated to generate
final analogues for biological evaluation against ACC inhibition.
Amide 49 is a representative example with an IC50 of 174 nM.24
Table 2. Lactam Cyclization
a
b
conditions
% yield of 39
t-BuLi (2 equiv), −78 °C
s-BuLi (2 equiv), −78 °C
s-BuLi (2 equiv), −42 °C
i-PrMgCl (1 equiv), −78 °C
Mg turnings (10 equiv), rt → reflux
99
96
99
0
CONCLUSION
■
0
Our interest in developing ACC inhibitors led us to explore a
number of pyrazole cores including an N-2 tert-butyl
spirolactam-based template. Challenges in synthesizing these
hitherto unknown scaffolds led to the exploration of several
reactions traditionally circumvented in an industrial setting due
to safety concerns upon scale-up. Rapid access to the lactam
provided a number of active compounds which underscored
our desire to access this structural motif. These successes led to
an internal campaign to optimize the route for efficiency and
safety. In this regard, an optimized reaction sequence of 10
steps from commercially available materials provided 40 in 27%
overall yield and facilitated advanced analogue production.
From a broader perspective, this work describes synthetic
access to fused pyrazolo spirolactams from halogenated
benzylic arenes and cyclic carboxylates and could be applied
to the synthesis of other spirocyclic systems.
a
Typical reaction conditions: Base was added to a 0.1 M solution of
isocyanate in THF at the designated temperature. After being stirred
b
for 1 h, the reaction was warmed to RT and quenched. Isolated yield.
butyllithium or tert-butyllithium at −78 °C afforded a high
yield of the desired spirolactam core. Running the reaction at
−42 °C was also successful in furnishing the desired C−C bond
and is more amenable to large-scale synthesis. In attempts to
replace the more pyrophoric organolithium reagents with i-
PrMgCl, addition of the Grignard reagent to the isocyanate was
observed. Treatment of 38 with Mg turnings also failed to
provide the desired product.
During our synthesis, tert-butyllithium was used to form
lactam 39 in quantitative yield on greater than a 15 g scale, and
the structure of the cyclization product was confirmed by
NOESY. Hydrogen chloride in dioxane was used to deprotect
the piperidine amine group and provide the HCl salt of the
lactam core in quantitative yield. This route provided the
lactam core with an overall yield of 27% over 10 steps from the
commercially available amino pyrazole. The spirolactam core
was then elaborated into ACC inhibitors via amide formation.20
EXPERIMENTAL SECTION
General Experimental Methods. All chemicals, reagents, and
■
solvents were purchased from commercial sources and used without
1
further purification. H NMR spectra were recorded with 400 or 500
MHz spectrometers and are reported relative to deuterated solvent
1
signals. Data for H NMR spectra are reported as follows: chemical
Scheme 8. Synthesis of N-1 i-Pr Lactam Core
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shift (δ ppm), multiplicity, coupling constant (Hz), and integration.
The multiplicities are denoted as follows: s, singlet; d, doublet; t,
triplet; q, quartet; spt, septet; m, multiplet; br s, broad singlet. 13C
NMR spectra were recorded at 100 or 125 MHz. Data for 13C NMR
spectra are reported in terms of chemical shift (δ ppm). IR spectra are
reported by frequency of absorption (cm−1). High resolution mass
spectrometry (HRMS) was performed via electrospray ionization
(ESI) source. The system used was an Agilent 1200 DAD (G1315C):
190−400 nm scan; 4 nm slit, and Agilent 6220 MS (TOF). Silica gel
chromatography was performed using a medium pressure Biotage or
ISCO system and columns prepackaged by various commercial
vendors including Biotage and ISCO. Whatman precoated silica gel
plates (250 μm) were used for analytical thin-layer chromatography
(TLC). The terms “concentrated” and “evaporated” refer to the
removal of solvent at reduced pressure on a rotary evaporator with a
water bath temperature not exceeding 60 °C.
Ethyl 3-Bromo-1H-pyrazole-4-carboxylate (29). A three-neck
flask equipped with a mechanical stirrer was charged with ethyl 3-
amino-1H-pyrazole-4-carboxylate (98.6 g, 635 mmol), CuBr2 (144 g,
640 mmol), and MeCN (1.27 L). The mixture was cooled in an ice
bath, and isoamyl nitrite (110 mL, 820 mmol) was added. After 15 min
of stirring at this temperature, the reaction was slowly warmed to an
internal temperature of 50 °C and stirred for 2 h. The dark green
reaction mixture was then cooled to room temperature, quenched with
a 1 M aqueous solution of HCl (700 mL), and washed with EtOAc.
The organic layer was washed with water and brine, dried over MgSO4,
filtered, and concentrated in vacuo to afford the desired product as a
thick, dark green oil (124 g) that was used without further purification.
For characterization purposes, an aliquot was purified by silica gel
chromatography (20−40% EtOAc/heptanes), and the desired product
was isolated as a white solid: 1H NMR (CDCl3, 500 MHz) δ 10.63 (br
s, 1H), 8.15 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H);
13C NMR (CDCl3, 125 MHz) δ 161.9, 135.0, 127.8, 114.0, 61.0, 14.5;
HRMS (ESI) m/z [M + 2 + H]+ calcd for C6H8BrN2O2, 220.9744,
found 220.9746; mp = 85−88 °C; IR: 3147, 2978, 1707, 1207, 1054,
769.
°C. The reaction was stirred for 1 h in the dry ice/acetone bath and 1
h in an ice bath. The mixture was cooled back to −78 °C, and EtOAc
(100 mL) was slowly added. A separate three-neck flask equipped with
a mechanical stirrer was charged with a saturated aqueous solution of
Rochelle’s salt (1.5 L). The organic solution was slowly poured with
stirring into the Rochelle’s salt solution, and the mixture was stirred at
room temperature for 1 h. The layers of the biphasic mixture were
separated, and the aqueous layer was washed with EtOAc. The
combined organics were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. The resulting material was purified
by silica gel chromatography (10−80% EtOAc/heptanes), and the
desired alcohol was isolated as clear oil (68.4 g, 46% over three steps):
1H NMR (CDCl3, 500 MHz) δ 7.48 (s, 1H), 4.51 (d, J = 5.9 Hz, 2H),
1.65 (t, J = 5.8 Hz, 1H), 1.55 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ
127.0, 125.5, 120.0, 59.7, 56.0, 29.8; HRMS (ESI) m/z [M + H]+ calcd
for C8H14BrN2O, 233.0284, found 233.0283; IR: 3367, 2978, 2876,
1553, 1410, 1369, 1216, 1004.
3-Bromo-1-tert-butyl-4-(chloromethyl)-1H-pyrazole (50).
Starting (pyrazol-4-yl)methanol 31 (45.6 g, 196 mmol) was dissolved
in dry DCM (1.00 L) and cooled in an ice bath. Et3N (38.1 mL, 273
mmol) was added followed by methylsulfonyl chloride (19.8 mL, 254
mmol). After being stirred for 15 min, the reaction was warmed to
room temperature and stirred for 2 h. The reaction was quenched with
water (1 L) and diluted with DCM. The phases were separated, and
the aqueous layer was extracted with DCM. The combined organics
were washed with brine, dried over MgSO4, filtered, and concentrated
in vacuo to afford the desired product as a clear oil (48.8 g) that was
used without further purification. For characterization purposes, an
aliquot was purified by silica gel chromatography (5−15% EtOAc/
heptanes), and the desired product was isolated as a clear oil: 1H NMR
(CDCl3, 500 MHz) δ 7.53 (s, 1H), 4.50 (s, 2H), 1.58 (s, 9H); 13C
NMR (CDCl3, 125 MHz) δ 127.6, 126.3, 117.3, 60.1, 36.7, 29.8;
HRMS (ESI) m/z [M + 2 + H]+ calcd for C8H13BrClN2, 252.9923,
found 252.9928; IR: 2979, 2938, 2910, 1552, 1402, 1369, 1213, 732.
3-Bromo-1-tert-butyl-4-(iodomethyl)-1H-pyrazole (32). Start-
ing 4-(chloromethyl)pyrazole 50 (48.6 g) was dissolved in acetone
(200 mL), and NaI (57.9 g, 386 mmol) was added. The suspension
was heated for 2 h at reflux. The brown suspension was cooled to
room temperature and concentrated to dryness. The resulting dark
brown solid was partitioned between EtOAc and water, the layers were
separated, and the aqueous phase was extracted with EtOAc. The
combined organics were washed with a saturated aqueous solution of
sodium thiosulfate, dried over MgSO4, filtered, and concentrated in
vacuo to afford the desired product as a yellow oil (58.6 g), which was
used without further purification. For characterization purposes, an
aliquot was purified by silica gel chromatography (5−10% EtOAc/
3-Bromo-1-tert-butyl-1H-pyrazole-4-carboxylic Acid (30). A
mixture of pyrazole 29 (124 g) and t-BuOH (252 g, 3.40 mmol) was
heated to 30 °C to give a homogeneous green solution. Concentrated
H2SO4 (54.2 mL, 1.01 mol) was slowly added, and the solution was
stirred at this temperature until bubbling stopped. The reaction
mixture was then heated to gentle reflux for 2.5 h, which caused the
solution to turn from green to brown. After being cooled to room
temperature, the reaction mixture was diluted with EtOAc. The
organic layer was washed with water, dried over MgSO4, filtered, and
concentrated in vacuo to afford a brown gum (149 g). NMR analysis
of this brown gum is consistent with a mixture (1:5) of the desired 3-
bromo-1-tert-butyl-1H-pyrazole-4-carboxylic acid (30) and its ethyl
ester. This mixture of carboxylic acid and ester (149 g) was used
without further purification. For characterization purposes, an aliquot
(240 mg, 1.44 mmol) was dissolved in THF (3 mL) and treated with a
1 M aqueous solution of LiOH (5 mL, 5 mmol) at 60 °C for 4 h. The
solution was acidified to pH of ∼3 with a 1 M aqueous solution of
HCl. The aqueous solution was washed with DCM. The organic layer
was washed with brine, dried over MgSO4, filtered, and concentrated
in vacuo to give the desired carboxylic acid as a white solid (320 mg,
90%). This white solid can be further purified by trituration in
1
heptanes), and the desired product was isolated as a yellow oil: H
NMR (CDCl3, 500 MHz) δ 7.53 (s, 1H), 4.29 (s, 2H), 1.57 (s, 9H);
13C NMR (CDCl3, 125 MHz) δ 127.0, 126.5, 118.3, 60.1, 29.8, −6.1;
HRMS (ESI) m/z [M + H]+ calcd for C8H13BrIN2, 342.9301, found
342.9299; IR: 2978, 2935, 1683, 1548, 1384, 1370, 1208.
1-tert-Butyl 4-Ethyl 4-(1-(carbonyl)piperidine-4-carbonyl)-
piperidine-1,4-dicarboxylate: Claisen Condensation Product
(35). For characterization purposes, the Claisen condensation product
35 was obtained during the optimization of the enolate formation
procedure (Table 1), purified by silica gel chromatography (0−40%
1
EtOAc/heptanes) and isolated as a clear oil: H NMR (CDCl3, 500
1
heptanes: H NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 1.62 (s, 9H);
MHz) δ 4.23 (q, J = 7.1 Hz, 2H), 4.07−4.18 (m, 2H), 3.69 (d, J = 10.7
Hz, 2H), 3.17−3.21 (m, 2H), 2.77−2.83 (m, 1H), 2.68 (br s, 2H),
2.20−2.08 (m, 2H), 1.82−1.93 (m, 2H), 1.51−1.68 (m, 4H), 1.45 (s,
9H), 1.45 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H)); 13C NMR (CDCl3, 125
MHz) δ 208.0, 171.1, 154.5, 154.5, 79.8, 79.7, 61.7, 59.6, 53.4, 44.6,
31.8, 29.5, 29.0, 28.4, 22.7, 14.1; HRMS (ESI) m/z [M + H]+ calcd for
C24H41N2O7, 469.2908, found 469.2915; IR: 2975, 1689, 1420, 1365,
1279, 1240, 1164, 1127, 1012, 979, 920, 866, 768, 731.
4-((3-Bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)-1-(tert-
butoxycarbonyl)piperidine-4-carboxylic Acid (37). A solution of
1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (33) (76.0 g, 290
mmol) in THF (250 mL) was added over 45 min to a 1 M solution
of LHMDS in THF (300 mL, 300 mmol) at 0 °C. After the reaction
13C NMR (CDCl3, 125 MHz) δ 167.3, 132.9, 128.0, 112.3, 60.9, 29.6;
HRMS (ESI) m/z [M + Na]+ calcd for C8H11BrN2NaO2, 268.9896,
found 268.9901; mp = 165−168 °C; IR: 2979, 2591, 1681, 1531, 1245,
1057, 768, 730. The regioselectivity was confirmed by NOESY NMR
(CDCl3, 500 MHz) between the tert-butyl group (1.62 ppm) and the
aromatic proton (8.05 ppm).
(3-Bromo-1-tert-butyl-1H-pyrazol-4-yl)methanol (31). A
three-neck flask was charged with the mixture of carboxylic acid and
ester obtained from the previous step (149 g) and THF (1.00 L). The
solution was cooled to −78 °C, and a 1.5 M solution of DIBAL in
toluene (1.08 L, 1.62 mol) was added over 30 min. During the
addition, the internal temperature was monitored to stay below −40
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mixture was stirred for 20 min, a solution of 4-(iodomethyl)pyrazole
32 (58.6 g) in THF (250 mL) was added over 45 min. During the
addition, the internal temperature was monitored to stay below 5 °C.
After being stirred for 15 min, the reaction was allowed to warm to
room temperature. The reaction was quenched with a saturated
aqueous solution of NH4Cl and diluted with water. The aqueous layer
was extracted with EtOAc. The organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The resulting orange oil was
dissolved in MeOH (825 mL), treated with a 6 M aqueous solution of
NaOH (825 mL, 4.90 mol), and heated at reflux for 18 h. The MeOH
and most of the water was removed in vacuo. The remaining solution
was diluted with EtOAc and water. The aqueous layer was extracted
with EtOAc. The combined organics were concentrated in vacuo to
give a peach-colored foam. This material was suspended in DCM (350
mL) and heptanes (100 mL) and stirred for 1 h. The sodium salt of
the desired product is a white insoluble solid, which was filtered and
washed with heptanes. The resulting white solid was dissolved in
water, treated with a 1 N aqueous solution of HCl, and extracted with
EtOAc. The organic phase was washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo to afford the desired product as a
container, the solutions were combined and fed to the jacketed, 275
mL coil flow reactor at a rate of 1.5 mL/min. The reactor residence
time was approximately 90 min, and the reactor was maintained at 120
°C and 500 psi. The resulting toluene solution was concentrated in
vacuo to a total of ∼200 mL. The solution was diluted with EtOAc
(350 mL) and washed with water (350 mL). The aqueous phase was
extracted with additional EtOAc (350 mL). The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to afford the crude material as a clear gum (28.9
g, 96%) that was used without further purification.
Boc-Protected Lactam 39 Using t-BuLi. Isocyanate 38 (17.7 g,
40.3 mmol) was dissolved in dry THF (400 mL) under nitrogen
atmosphere. The solution was cooled to −78 °C and a 1.7 M solution
of t-BuLi in pentane (47.4 mL, 80.5 mmol) was added dropwise. The
mixture was stirred in the dry ice/acetone bath for 1 h and was then
allowed to warm to room temperature. After a total of 1.5 h, the
reaction was quenched with a saturated aqueous solution of NH4Cl
and stirred for 15 min. The reaction mixture was diluted with water
(750 mL), EtOAc (1.75 L), and DCM (500 mL). The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The
desired lactam was isolated as a yellowish solid (14.6 g, 99%) and was
1
fluffy white solid (57.3 g, 63% over four steps): H NMR (CD3OD,
1
used without further purification. The H NMR of this material was
400 MHz) δ7.44 (s, 1H), 3.88 (dt, J = 13.7, 3.3 Hz, 2H), 2.84−2.95
(m, 2H), 2.66 (s, 2H), 2.01 (d, J = 13.9 Hz, 2H), 1.51 (s, 9H), 1.43 (s,
9 H), 1.36−1.40 (m, 2H); 13C NMR (CD3OD, 100 MHz) δ 177.2,
155.3, 127.7, 127.2, 115.1, 79.9, 59.4, 47.2, 46.8, 34.0, 32.8, 28.5, 27.5;
HRMS (ESI) m/z [M + Na]+ calcd for C19H30BrN3NaO4, 468.1294,
found 468.1293; mp = 177−181 °C; IR: 3133, 2976, 2929, 1727, 1694,
1429, 1367, 1172.
1-tert-Butyl 4-Ethyl 4-((3-Bromo-1-tert-butyl-1H-pyrazol-4-
yl)methyl)piperidine-1,4-dicarboxylate (34). For characterization
purposes, prior to hydrolysis with NaOH, a sample from the enolate
alkylation reaction was subjected to purification by silica gel
chromatography (0−75% EtOAc/heptanes). The desired product 34
was isolated as a clear oil: 1H NMR (CDCl3, 400 MHz) δ 7.15 (s, 1H),
4.15 (q, J = 7.1 Hz, 2H), 3.92 (d, J = 13.4 Hz, 2H), 2.87 (t, J = 11.7
Hz, 2H), 2.66 (s, 2H), 2.09 (d, J = 12.9 Hz, 2H), 1.54 (s, 9H), 1.40−
1.50 (m, 11H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
δ 175.3, 155.1, 127.6, 126.6, 115.1, 79.7, 60.9, 59.5, 47.2, 41.7, 34.6,
33.2, 29.8, 28.7, 14.5; HRMS (ESI) m/z [M + Na]+ calcd for
C21H34BrN3NaO4, 494.1625, found 494.1621; IR: 2977, 1722, 1686,
1421, 1388, 1366, 1277, 1211, 1170, 1091, 1074, 1025, 965, 865, 729,
647.
comparable to an analytically pure sample: white solid, purified by
1
silica gel chromatography (0−5% MeOH/DCM); H NMR (CDCl3,
500 MHz) δ 7.39 (s, 1H), 5.88 (s, 1H), 3.53−3.68 (m, 2H), 3.34−3.39
(m, 2H), 2.81 (s, 2H), 1.67−1.82 (m, 4H), 1.64 (s, 9H), 1.47 (s, 9H);
13C NMR (CDCl3, 125 MHz) δ 162.3, 154.8, 141.1, 123.8, 117.9, 80.2,
60.1, 55.0, 39.8, 36.8, 31.2, 30.1, 28.6; HRMS (ESI) m/z [M + H]+
calcd for C19H31N4O3, 364.2421, found 364.2427; mp = 267−269 °C;
IR: 3221, 2976, 2936, 1672, 1423, 1159, 566.
Boc-Protected Lactam 39 Using s-BuLi. Isocyanate 38 (300 mg,
0.68 mmol) was dissolved in dry THF (5 mL) under nitrogen
atmosphere. The solution was cooled to −42 °C, and a 1.3 M solution
of s-BuLi in cyclohexane (1.1 mL, 1.4 mmol) was added dropwise. The
mixture was stirred in the dry ice/MeCN bath for an additional 15
min. The reaction was quenched with a saturated aqueous solution of
NH4Cl and was then allowed to warm to room temperature. The
reaction mixture was diluted with water (3 mL) and DCM (20 mL).
The layers were separated, and the aqueous layer was extracted with
DCM (15 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The desired lactam was isolated as
a white solid (250 mg, 99%) and was used without further purification.
Lactam 40. Boc-protected lactam 39 (18.7 g, 51.6 mmol) was
dissolved in DCM (500 mL). A 4 M solution of HCl in dioxane (130
mL, 516 mmol) was added, and the reaction was stirred at room
temperature for 30 min. The clear solution turned into a white
suspension. The solvent was removed in vacuo to afford the desired
product as a white solid (17.2 g, 99%), which was used without further
purification. The 1H NMR of this material was comparable to an
analytically pure sample: white solid, purified by trituration in DCM;
1H NMR (DMSO-d6, 500 MHz) δ 8.99 (br s, 2H), 7.93 (s, 1H), 7.75
(s, 1H), 3.14−3.24 (m, 2H), 3.01−3.12 (m, 2H), 2.77 (s, 2H), 1.72−
1.90 (m, 4H), 1.52 (s, 9H); 13C NMR (DMSO-d6, 125 MHz) δ 161.8,
141.3, 125.4, 117.9, 59.8, 53.2, 39.8, 33.5, 31.0, 30.2; HRMS (ESI) m/z
[M + H]+ calcd for C14H23N4O, 263.1866, found 263.1869; mp =
328−336 (decomposition) °C; IR: 3419, 2977, 2802, 1662, 1490,
1207.
2′-(tert-Butyl)-1-(1H-indazole-5-carbonyl)-4′,6′-
dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-
one (41). 1H-Indazole-5-carboxylic acid (100 mg, 0.617 mmol) was
dissolved in DMF (6 mL). Lactam 40 (207 mg, 0.617 mmol) and
Et3N (0.43 mL, 3.1 mmol) were added, and the solution was stirred at
room temperature for 15 min. A 50% solution of propylphosphonic
anhydride in EtOAc (0.41 mL, 0.68 mmol) was added, and the
reaction mixture was stirred for 16 h. The reaction mixture was diluted
with a saturated aqueous solution of NaHCO3 and water and then
extracted with DCM. The combined organic phases were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. The
crude material was purified by silica gel chromatography (0−50% of
20% MeOH in DCM/DCM) to afford 41 as a white solid (150 mg,
tert-Butyl 4-((3-Bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)-
4-isocyanatopiperidine-1-carboxylate (38). A three-neck flask,
equipped with a mechanical stirrer, was charged with carboxylic acid
37 (15.8 g, 35.5 mmol) and toluene (120 mL). Et3N (4.94 mL, 35.5
mmol) and diphenylphosphoryl azide (8.17 mL, 37.2 mmol) were
added. The heterogeneous mixture was heated to an internal
temperature of 85 °C and stirred for 2 h. The reaction mixture was
then cooled to room temperature and diluted with EtOAc and water.
The organic layer was washed with water, and the combined aqueous
layers were extracted with EtOAc. The combined organics were
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo to afford the desired product as a clear gum (14.2 g, 91%) that
1
was used without further purification. The H NMR of this material
was comparable to an analytically pure sample: clear gum, purified by
silica gel chromatography (5−40% EtOAc/heptanes); 1H NMR
(CDCl3, 400 MHz) δ 7.39 (s, 1H), 4.01 (br s, 2H), 2.95 (br s,
2H), 2.67 (s, 2H), 1.60−1.62 (m, 4H), 1.56 (s, 9H), 1.44 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ 154.8, 127.7, 127.6, 122.9, 113.9, 80.0,
60.8, 59.8, 40.2, 38.2, 37.1, 29.8, 28.6; HRMS (ESI) m/z [M + 2 +
NH4]+ calcd for C19H33BrN5O3, 460.1743, found 460.1740; IR: 2976,
2255, 1691, 1419, 1245.
Set-up and Conditions for Formation of tert-Butyl 4-((3-
Bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)-4-isocyanatopi-
peridine-1-carboxylate (38) by Flow Chemistry. A solution of
carboxylic acid 37 (30.0 g, 53.3 mmol) and Et3N (9.40 mL, 63.7
mmol) in toluene (150 mL) was placed in a glass bottle. In a separate
glass container, diphenylphosphoryl azide (18.0 mL, 82.2 mmol) was
dissolved in toluene (180 mL). Using an ISCO syringe pump for each
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The Journal of Organic Chemistry
Article
60%): 1H NMR (DMSO-d6, 500 MHz) δ 13.23 (s, 1H), 8.14 (s, 1H),
7.81 (s, 1H), 7.73 (s, 1H), 7.70 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.36
(d, J = 8.7 Hz, 1H), 3.37−3.94 (br m, 4H), 2.81 (s, 2H), 1.67 (br s,
4H), 1.51 (s, 9H); 13C NMR (125 MHz, DMSO-d6) δ 170.1, 161.9,
141.6, 140.6, 135.0, 128.8, 125.9, 125.2, 122.8, 120.4, 118.2, 110.8,
59.7, 55.2, 36.8, 30.3, 30.1; HMS (ESI) m/z [M + H]+ calcd for
C22H26N6O2, 407.2190, found 407.2191; mp = 184−184 °C; IR: 3230,
2977, 2941, 1669, 1623, 1439.
328.9145, found 328.9130; IR: 2978, 2935, 1543, 1418, 1395,
1242,1198, 1157, 996, 728, 675.
4-((5-Bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-1-(tert-
butoxycarbonyl)piperidine-4-carboxylic Acid (46). Carboxylic
acid 46 was prepared from ester 33 (1.13 g, 4.39 mmol) and iodide 45
(850 mg, 2.58 mmol) using the protocol described for compound 37.
The desired material was isolated as a white solid (831 mg, 75%) that
was analytically pure: 1H NMR (DMSO-d6, 500 MHz) δ 7.40 (s, 1H),
4.60 (spt, J = 6.6 Hz, 1H), 3.71 (d, J = 12.0 Hz, 2H), 2.84 (br s, 2H),
2.54 (s, 2H), 1.86 (d, J = 12.9 Hz, 2H), 1.35 (s, 9H), 1.34 (d, J = 6.6
Hz, 6H), 1.16−1.22 (m, 2H); 13C NMR (DMSO-d6, 125 MHz) δ
159.4, 145.3, 145.2, 121.0, 118.3, 84.0, 83.9, 56.4, 51.4, 39.3, 38.0, 33.5,
27.4; HRMS (ESI) m/z [M + Na]+ calcd for C18H28BrN3NaO4,
452.1155, found 452.1137; IR: 3452, 2976, 1689, 1551, 1477, 1424,
1393, 366, 1277, 1246, 1172, 1150, 1075, 1000, 965, 865, 736.
tert-Butyl 4-((5-Bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-
4-isocyanatopiperidine-1-carboxylate (47). Isocyanate 47 was
prepared from carboxylic acid 46 (400 mg, 0.93 mmol) using the
protocol described for compound 38. The desired material was
isolated as a clear oil which solidified upon standing (372 mg, 94%)
Ethyl 5-Amino-1-isopropyl-1H-pyrazole-4-carboxylate (43).
N-Isopropylhydrazine (3.45 g, 31.2 mmol), ethyl (ethoxymethylene)-
cyanoacetate (5.41 g, 31.0 mmol), and K2CO3 (4.33 g, 31.3 mmol)
were dissolved in EtOH (100 mL), and the reaction mixture was
heated to reflux for 6 h. The reaction was cooled to room temperature,
and the solvent was removed in vacuo. The residue was partitioned
between water and EtOAc. The aqueous layer was extracted with
EtOAc. The combined organics were washed with water and brine,
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (0−85% EtOAc/heptanes),
and the desired aminopyrazole was isolated as clear gum (3.77 g,
1
61%): H NMR (CDCl3, 400 MHz) δ 7.63 (s, 1H), 5.05 (br s, 2H),
4.24 (q, J = 7.2 Hz, 2H), 4.20 (spt, J = 6.6 Hz, 1H), 1.45 (d, J = 6.6 Hz,
6H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 164.8,
148.4, 139.1, 96.3, 59.7, 48.7, 21.6, 14.7; HRMS (ESI) m/z [M + H]+
calcd for C9H16N3O2, 198.1237, found 198.1237; IR: 2975, 1691,
1158, 730.
1
and was analytically pure: H NMR (CDCl3, 500 MHz) δ 7.48 (s,
1H), 4.69 (spt, J = 6.6 Hz, 1H), 4.02 (br s, 2H), 2.96 (br s, 2H), 2.68
(s, 2H), 1.63−1.70 (m, 2H), 1.54−1.624 (m, 2H), 1.48 (d, J = 6.6 Hz,
6H), 1.45 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 154.8, 140.4,
130.3, 114.3, 114.1, 80.1, 60.5, 52.1, 40.0, 38.4, 37.1, 28.6, 22.3; HRMS
(ESI) m/z [M + Na]+ calcd for C18H27BrN4NaO3, 449.1159, found
449.1166; IR: 3979, 2363, 2258, 1694, 1420, 1366, 1247, 1174, 1148,
1000, 967.
Ethyl 5-Bromo-1-isopropyl-1H-pyrazole-4-carboxylate (44).
Starting amino pyrazole 43 (3.76 g, 19.1 mmol) was dissolved in
MeCN (40 mL). Copper(II) bromide (6.29 g, 28.0 mmol) and
isoamyl nitrite (3.45 mL, 24.8 mmol) were added, and the reaction
mixture was heated to 50 °C for 4.5 h. The reaction was cooled to
room temperature and quenched with a 1 M aqueous solution of HCl.
The aqueous layer was extracted with EtOAc. The combined organics
were dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel chromatography (0−50% EtOAc/
heptanes), and the desired bromopyrazole was isolated as clear oil
(4.14 g, 83%): 1H NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 4.81 (spt,
J = 6.7 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.50 (d, J = 6.6 Hz, 6H),
1.37 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 162.3, 142.2,
116.6, 113.5, 60.5, 52.2, 22.2, 14.6; HRMS (ESI) m/z [M + Na]+ calcd
for C9H13BrNaN2O2, 283.0053, found 283.0052; IR: 2981, 2939, 1720,
1532, 1409, 1214, 1046.
(5-Bromo-1-isopropyl-1H-pyrazol-4-yl)methanol (51). Pyra-
zole 51 was prepared from ester 44 (4.14 g, 15.9 mmol) using the
protocol described for compound 31. The desired material was
purified by silica gel chromatography (0−75% EtOAc/heptanes) and
isolated as a white solid (3.21 g, 92%): 1H NMR (CDCl3, 500 MHz) δ
7.60 (s, 1H), 4.68 (spt, J = 6.6 Hz, 1H), 4.52 (s, 2H), 1.95 (br s, 1H),
1.48 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 139.5, 120.4,
112.4, 55.9, 51.9, 22.3; HRMS (ESI) m/z [M + H]+ calcd for
C7H12BrN2O, 219.0128, found 219.0124; IR: 3333, 2980, 2936, 2874,
1553, 1400, 1369, 1346, 1248, 1183, 1084, 993, 855, 755, 675.
5-Bromo-1-isopropyl-4-(chloromethyl)-1H-pyrazole (52).
Chloride 52 was prepared from alcohol 51 (1.59 g, 7.26 mmol)
using the protocol described for compound 50. The desired material
was purified by silica gel chromatography (7−60% EtOAc/heptanes)
and isolated as a clear oil (1.39 g, 81%): 1H NMR (CDCl3, 500 MHz)
δ 7.63 (s, 1H), 4.68 (spt, J = 6.7 Hz, 1H), 4.50 (s, 2H), 1.49 (d, J = 6.6
Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 139.8, 117.5, 113.4, 52.2,
36.7, 22.3; IR: 2981, 1550, 1420, 1399, 1262, 1242, 1203, 996, 901,
737, 707. Due to instability of the product, HRMS could not be
attained.
Boc-Protected Lactam (53). Lactam 53 was prepared from
isocyanate 47 (372 mg, 0.87 mmol) using the protocol described for
compound 39 using t-BuLi. The desired material was purified by silica
gel chromatography (0−80% EtOAc/heptanes) and isolated as a white
1
solid (271 mg, 89%): H NMR (CDCl3, 500 MHz) δ 7.36 (s, 1H),
6.57 (s, 1H), 5.46 (spt, J = 6.7 Hz, 1H), 3.57 (d, J = 12.9 Hz, 2H),
3.41−3.47 (m, 2H), 2.80 (s, 2H), 1.65−1.81 (m, 4H), 1.48 (d, J = 6.8
Hz, 6H), 1.45 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 159.7, 154.8,
135.6, 128.9, 120.3, 80.1, 55.3, 52.2, 39.7, 36.7, 31.5, 28.6, 22.7; HRMS
(ESI) m/z [M + H]+ calcd for C18H29N4O3, 349.2234, found
349.2236; IR: 3230, 2975, 1666, 1551, 1502, 1422, 1365, 1274, 1247,
1158, 779.
Lactam 48. Lactam 48 was prepared from compound 53 (3.82 g,
11.0 mmol) using the protocol described for compound 40. The
desired material was isolated as a white solid (3.48 g, 99%): 1H NMR
(DMSO-d6, 500 MHz) δ 9.23 (br s, 1H), 9.12 (br s, 1H), 8.10 (s, 1H),
7.39 (s, 1H), 5.39 (spt, J = 6.7 Hz, 1H), 3.13−3.27 (m, 2H), 2.98−
3.11 (m, 2H), 2.80 (s, 2H), 1.78−1.94 (m, 4H), 1.36 (d, J = 6.6 Hz,
6H); 13C NMR (DMSO-d6, 125 MHz) δ 159.3, 135.9, 129.3, 120.3,
53.7, 51.5, 39.8, 33.2, 30.9, 23.1; HRMS (ESI) m/z [M + H]+ calcd for
C13H21N4O, 249.171, found 249.1712; IR: 3388, 3975, 2802, 1667,
1502, 1427, 1393, 1335, 1305, 1130, 1049, 3779, 667.
1-(1H-Indazole-5-carbonyl)-1′-isopropyl-4′,6′-dihydrospiro-
[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one (49). Amide
49 was prepared from 1H-indazole-5-carboxylic acid (100 mg, 0.617
mmol) and lactam 48 (198 mg, 0.616 mmol) using the protocol
described for compound 41. The desired material was purified by silica
gel chromatography (0−50% of 20% MeOH in DCM/DCM) to afford
49 as a white solid (188 mg, 78%): 1H NMR (DMSO-d6, 500 MHz) δ
13.23 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.57 (d, J = 8.5
Hz, 1H), 7.39 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 5.41 (sept, J = 6.5 Hz,
1H), 3.49−3.85 (br m, 4H), 2.84 (s, 2H), 1.69 (br s, 4H), 1.36 (d, J =
6.6 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 170.1, 159.4, 140.6,
135.9, 135.0, 129.5, 128.7, 125.9, 122.8, 120.5, 120.4, 110.8, 55.7, 51.5,
36.7, 31.9, 30.3, 23.1; HRMS (ESI) calcd for C21H25N6O2 (m/z) [M +
H]+ 393.2034, found 393.2045; mp = 148−150 °C; IR: 3225, 2941,
1666, 1609, 1439.
5-Bromo-1-isopropyl-4-(iodomethyl)-1H-pyrazole (45). Io-
dide 45 was prepared from chloride 52 (913 mg, 3.84 mmol) using
the protocol described for compound 32. The desired material was
purified by silica gel chromatography (0−30% EtOAc/heptanes) and
1
isolated as a clear oil (1.04 g, 82%): H NMR (CD2Cl2, 500 MHz) δ
7.60 (s, 1H), 4.66 (spt, J = 6.7 Hz, 1H), 4.33 (s, 2H), 1.46 (d, J = 6.8
Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 145.4, 124.5, 119.0, 58.1,
28.3, 0.00; HRMS (ESI) m/z [M + H]+ calcd for C7H11BrIN2,
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Article
proton of the pyrazole ring in comparison to the N2-t-Bu analogue
where a signal was observed.
(24) For assay conditions, see ref 3.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Elnaz.Menhaji-Klotz@Pfizer.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Vincent Mascitti and Dan Kung for helpful
discussions as well as Bill Esler and Kim McClure for their help
with the manuscript.
REFERENCES
■
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