Efficient and scalable synthesis of 3,5,7-trisubstituted 1H-indazoles as potent IKK2 inhibitors

Article abstract of DOI:10.1055/s-0028-1087364

Efficient and scalable chemical approaches to 3,5,7-trisubstituted 1H-indazoles were developed and applied to the synthesis of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate, a key intermediate for 3,5,7-trisubstit

Full text of DOI:10.1055/s-0028-1087364

3216
LETTER
Efficient and Scalable Synthesis of 3,5,7-Trisubstituted 1H-Indazoles as Potent
IKK2 Inhibitors
S
ynthesis of 3,5,7-
i
T
risubs
c
tituted 1
H
-
Indazole
s
en Lin,*a Jakob Busch-Petersen,a Jianghe Deng,a Christine Edwards,b Zhaoguo Zhang,c Jeffrey K. Kernsa
a
Respiratory Center of Excellent Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
Fax +1(610)2704451; E-mail: Xichen.2.Lin@gsk.com
b
c
Argenta Discovery Ltd. , 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK
School of Chemistry and Chemical Engineering, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240, P. R. of China
Received 11 March 2008
ther decreased on a larger scale, which limited the supply
of a key intermediate 4. In order to fully explore the SAR
of the new series, we required an efficient and scalable
synthetic process. In this report, we describe two synthetic
Abstract: Efficient and scalable chemical approaches to 3,5,7-
trisubstituted 1H-indazoles were developed and applied to the syn-
thesis of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-
indazol-3-yl]-1-piperidinecarboxylate, a key intermediate for 3,5,7-
trisubstituted 1H-indazole, which was identified as a potent IKK2 routes, which provided us compound 4 in a hundred-gram
inhibitor. The sequence allows for a scalable preparation of the tar-
scale.
get compound in eight steps and proceeds in 40% overall yield from
readily available starting material.
O
Br
Key words: cyclization, IKK2 inhibitors, indazole, lithiation,
a
Br
organometallic reagents
~10–20%
O
F
N
Boc
F
N
N
O
The transcription factor NF-kB mediates the expression
of a number of pro-inflammatory cytokines, adhesion
molecules, growth factors, and anti-apoptosis survival
proteins.1 NF-kB is inhibited by IkB proteins in the cyto-
plasm. Various cellular stress and pro-inflammatory stim-
uli triggers the degradation of IkB proteins; thereby
stimulating the translocation of NF-kB into the nucleus
and the production of pro-inflammatory cytokines, such
as interleukin-1 (IL-1) and tumor necrosis factor alpha
(TFN-a). The proteolytic destruction of IkB via the
ubquitin-proteasome pathway is activated by the IkB
kinase complex (IKK) via its phosphorylation of IkB.2 In
studies using genetic mutants, it was shown that IKK2 of
the IKK complex plays an essential role in the phosphory-
lation of IkB.3 As a result, control of NF-kB release,
through IKK2 inhibition, could provide an effective treat-
ment of inflammatory diseases.
N
N
1
2
Boc
6
Boc
N
Boc
N
Br
c
b
Br
N
~ quant.
70%
N
H
N
N
H
N
H2N
O
4
3
SO2Et
N
In our ongoing research program for novel IKK2 inhibi-
tors, 3,5,7-trisubstituted 1H-indazole 5 was identified as a
potent IKK2 inhibitor.4 Our initial synthesis started with
5-bromo-2-fluorobenzonitrile (1, Scheme 1). The activat-
ed fluorobenzene 1 was lithiated ortho to the fluorine, and
the resulting aryllithium was reacted with Weinreb amide
6 to provide ketone 2.5 Compound 2 was then treated with
hydrazine hydrate in refluxing ethanol to give indazole 3
in quantitative yield.6 Hydrolysis of the cyano group to the
primary amide, followed by Suzuki coupling and sulfon-
amide formation provided the IKK2 inhibitor 5. However,
the initial step in Scheme 1 proceeded in very low yield
(ca. 10–20%) at a hundred-milligram scale. The yield fur-
N
N
H
H2N
O
5
Scheme 1 Reagents and conditions: (a) LDA, THF, –78 °C; Weinreb
amide 6; (b) NH2NH2, EtOH, reflux; (c) KOH, t-BuOH, reflux.
The initial effort focused on an optimization of the exist-
ing synthesis, mainly the first step. We replaced the C7-
nitrile moiety with tert-butyl ester or bis(Boc) amide
(Figure 1), hoping the bulkiness of the functionalities will
minimize the side product presumably resulting from ad-
dition of the aryllithium species to the C7-nitrile. Unfor-
tunately, neither of these approaches provided improved
yield; either starting material or complex mixtures were
SYNLETT 2008, No. 20, pp 3216–3220
1
6
.1
2
.2
0
0
8
Advanced online publication: 24.11.2008
DOI: 10.1055/s-0028-1087364; Art ID: S02308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3,5,7-Trisubstituted 1H-Indazoles
3217
Br
The optimized procedure in Scheme 2 produced ketone 2
from benzonitrile 1 in three steps and improved the over-
all yield to 30% compared to the original 10–20%. Fur-
thermore, the reaction could be carried out at 50 g scale to
produce enough key intermediate for further studies.
However, the synthetic procedure was still very challeng-
ing and labor intensive, since the first two steps required
six sequential low temperature operations, and the synthe-
sis was moisture and air sensitive.8,9
Br
O
F
F
O
N
O
O
O
O
O
Figure 1 Activated fluorobenzene with tert-butyl ester or bis(Boc)
amide
With practical concerns in mind, a more convenient route
to the target indazole via diazotization was then ex-
plored.10,11 Dimethyl aniline 10 was diazotized in acetic
acid to cyclize and form indazole 11 in 64% yield
obtained. Modification of the coupling partner by using
the corresponding aldehyde or an alkyl halide rather than
the Weinreb amide was also not successful.
It was envisaged that iodination ortho to fluorine, fol-
lowed by a selective metal–iodine exchange and quench
with a suitable piperidine carboxaldehyde might provide
a better overall yield of the desired coupling product.
However, direct iodination ortho to the fluorine with I2
and NaOH in DMF was not successful. Instead, TMP-
zincate methodology7 was employed: 5-bromo-2-fluo-
robenzonitrile (1) was treated with LiEt2ZnTMP generat-
ed in situ to produce the corresponding aryldiethyl
zincate, which was subsequently quenched with an excess
of I2 to produce 5-bromo-2-fluoro-3-iodobenzonitrile (7)
in excellent yield (Scheme 2).8 Compound 7 was treated
with isopropylmagnesium bromide and the resulting
Grignard reagent was mixed with Boc-protected piperi-
dine carboxaldehyde 9 in the presence of CeCl3 to provide
alcohol 8 in 52% yield.9 The alcohol was then oxidized us-
ing Swern or TEMPO/TCIA conditions to give the key in-
termediate 2, which was used as described in the original
synthesis.
Br
Br
a
N
64%
N
H
NH2
Br
11
10
Br
N
N
X b
c
H
14
Br
Br
N
N
N
N
H
H
HO
O
Br
13
12
Scheme 3 Reagents and conditions: (a) NaNO2, AcOH; (b) CrO3,
AcOH or KMnO4, H2O, i-PrOH; (c) NBS, (PhCO2)2, CHCl3.
Br
b
Br
a
N
95%
Br
95%
Br
I
a
b
N
NH2
H
75%
52%
Br
16
Br
F
F
O
Boc
15
N
H
N
N
N
1
7
9
I
Boc
c
Br
Br
61–80%
OH
N
O
N
Br
N
c
N
Br
H
H
O
Br
75%
N
Br
18
B
N-Boc
Boc
N
Boc
F
O
Boc
F
17
20
N
Boc
N
8
2
N
N
Boc
N
d
e
Br
Br
30–70%, 2 steps
60%, 3 steps
N
N
Br
N
N
N
H
Boc
N
H2N
O
H
HO
O
H2N
O
19
4
4
Scheme 4 Reagents and conditions: (a) KNO2, AcOH, 0 °C to r.t.;
(b) NaOH, I2, DMF; (c) Pd(Ph3P)4, K2CO3, DME–H2O, 80 °C; (d)
(BOC)2O, TEA, DMAP, CH2Cl2, r.t.; t-BuLi, CO2, THF, –78 °C to
r.t.; (e) NaHCO3, 120 °C; EDC, HOBt, NH3; PtO2, H2, r.t.
Scheme 2 Reagents and conditions: (a) LiEt2ZnTMP, I2, –70 °C;
(b) i-PrMgBr, CeCl3, aldehyde 9, –70 °C; (c) TEMPO, KBr,
NaHCO3; trichloroisocyanauric acid.
Synlett 2008, No. 20, 3216–3220 © Thieme Stuttgart · New York

3218
X. Lin et al.
LETTER
(Scheme 3). Unfortunately, oxidation of the methyl group group, presumably at the allylic position of the piperidine
in indazole 11 could not be accomplished using standard ring according to NMR and LCMS.14 Despite a consider-
oxidation conditions such as CrO3/AcOH or KMnO4/ able effort to optimize the reaction conditions by modify-
H2O/i-PrOH. It was hoped that bromination of the methyl ing temperature and quantity of tert-BuLi reagent, we
group followed by oxidation may be an alternative meth- were unable to reproducibly obtain compound 19 in a high
od for the formation of the desired carboxylic acid 12. yield. Chemoselective reduction of the double bond of
However, treatment of indazole 11 with NBS and diben- compound 18 in the presence of two bromines was not
zoyl peroxide in refluxing chloroform led to bromination successful either. However, with compound 19 in hand,
of C3 to produce 14, rather than the desired compound 13. we decided to continue the synthetic sequence. Therefore,
selective deprotection of the N1-Boc group, EDC/HOBt-
mediated carboxylic acid/ammonia coupling, and finally
An alternative method to introduce the desired carboxylic
group would be via direct lithiation of the C7 position
selective hydrogenation of the double bond in the pres-
(Scheme 4).12 Starting from 2,4-dibromo-6-methylaniline
ence of the C5 bromide provided the desired product 4.
(15), diazotization in acetic acid, followed by a spontane-
ous cyclization provided indazole 16 in excellent yield. In order to overcome the difficulty of the selective lithia-
Iodination using iodine/NaOH in DMF regioselectively tion step in Scheme 4, we decided to introduce the piperi-
afforded 3-iodoindazole 17,13 which underwent Suzuki dine ring earlier in the synthesis and to avoid Suzuki
coupling with boronic ester 20 to yield the coupling prod- coupling which gave rise to the problematic double bond
uct 18. The Boc protection of the N-1 nitrogen, followed (Scheme 5). The piperidine 22 was synthesized by
by regioselective metal–halogen exchange, at C7 and sub- Horner–Wadsworth–Emmons coupling of piperidone 27
sequent quench with dry ice provided the desired indazole with o-nitrobenzylphosphonate, which was readily avail-
7-carboxylic acid 19. The yield of the lithiation step var- able by treatment of o-nitrobenzyl bromide (21) under
ied to provide compound 19 in as high as 70% yield on a Arbuzov conditions.15 Simultaneous hydrogenation of
hundred-milligram scale, and as low as 30% on a gram the styrene double bond and the nitro group, followed by
scale. The major byproduct contained an extra carboxylic bromination with NBS provided dibromo aniline 24.16,17
Boc
N
Boc
N
a
b
Br
85% 2 steps
90%
NO2
NO2
NH2
Boc
N
21
22
23
O
27
Boc
Boc
N
N
Br
Br
c
d
N
90%
90%
NH2
N
H
Br
24
Br
25
Boc
N
Boc
N
Br
Br
e
f
N
N
65–75%, 2 steps
90%
N
N
H
H
HO
O
H2N
O
4
26
Scheme 5 Reagents and conditions: (a) P(OEt)3, toluene, reflux; piperidone 27, NaH, THF, 0 °C to r.t.; (b) Pd/C, H2, EtOH; (c) NBS, CH2Cl2;
(d) NaNO2, AcOH; (e) (BOC)2O, TEA, DMAP; n-BuLi, CO2, –78 °C to r.t., NaOH; (f) EDC, HOBt, NH3.
Synlett 2008, No. 20, 3216–3220 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,5,7-Trisubstituted 1H-Indazoles
3219
(162.6 g, 0.63 mol) in THF (300 mL) was added. The
Diazotization of the aniline in acetic acid, followed by a
spontaneous cyclization afforded the desired key com-
pound 25 in excellent yield.18 It is worth noting that direct
diazotization of aniline 23 provided much lower cycliza-
tion yield than what was observed with compound 24
which bears two electron-withdrawing groups on the phe-
nyl ring.19 Without the double bond in the piperidine ring,
Boc protection and metal–halogen exchange with t-BuLi
under direction of the neighboring Boc group proceeded
smoothly to provide the desired carboxylic acid 26 in a
two-step 75% yield. Upon further investigation, we were
pleased to find that n-BuLi also provided a similar two-
step yield (65%), which is very beneficial in a large-scale
reaction setting.20 Finally, a standard EDC/HOBt amide
formation provided the desired 3,5,7-trisubstituted 1H-
indazole 4.21 We repeated the synthetic sequence on a 500
gram scale and a similar overall yield was achieved.
reaction was left to warm to r.t. and stirred overnight. The
reaction was quenched with NaHSO3 (sat. 35 mL) and
filtered. The solvent was removed in vacuo and the resulting
residue was re-dissolved with EtOAc. The organic layer was
washed with NaHSO3 (sat.), brine, and dried over MgSO4.
The solvent was removed and the solid was recrystallized
from EtOAc–PE to provide the desired compound 7 (44.9 g,
75%). 1H NMR (400 MHz, CDCl3): d = 8.13 (dd, 1 H,
J = 4.8, 2.0 Hz), 7.74 (dd, 1 H, J = 4.8, 2.0 Hz).
(9) Procedure of the Preparation of Compound 8
To a solution of iodide 7 (45 g, 0.138 mol) in THF (100 mL)
was added i-PrMgBr (1.19 M in THF, 143 mL) at –60 °C in
0.5 h. The reaction mixture was stirred at –60 °C for 2 h.
Meanwhile, a suspension of anhyd CeCl3 (40.8 g, 0.17 mol)
in THF (500 mL) was stirred vigorously for 2 h at r.t. until it
became a milky white suspension mixture and then cooled to
–60 °C. To the CeCl3 suspension was added the above-
mentioned Grignard reagent and the mixture was stirred at
–60 °C for 0.5 h and –40 °C for 0.5 h. The resulting mixture
was recooled to –60 °C and N-Boc-4-formylpiperidine (35.3
g, 0.17 mol) in THF (150 mL) was added via cannula. The
reaction was warmed slowly to r.t. and stirred overnight. The
reaction was quenched with NaHCO3 (sat.) and dried over
Na2SO4. The solution was removed, and the residue was
purified by column chromatography with EtOAc–hexane
(1:1) to provide the desired product 8 (30 g, 53%). 1H NMR
(400 MHz, CDCl3): d = 7.88 (dd, 1 H, J = 6.4, 2.8 Hz), 7.64
(dd, 1 H, J = 6.4, 2.8 Hz), 4.83 (s, 1 H), 4.23–4.00 (m, 2 H),
2.71–2.50 (m, 3 H), 1.80–1.67 (m, 2 H), 1.39 (s, 9 H), 1.38–
1.25 (m, 2 H).
In summary, we have devised a practical and scalable syn-
thesis to access a key intermediate indazole 4. A 40%
overall yield was obtained in a large-scale synthesis,
which provided an important template for our ongoing
IKK2 inhibitor program.
Acknowledgment
We thank Drs. Katherine L. Widdowson and James F. Callahan for
helpful comments and discussions.
(10) For reviews, see: (a) Elguero, J. In Comprehensive
Heterocyclic Chemistry, Vol. 5; Katrizky, A. R.; Rees,
C. W., Eds.; Pergamon Press: New York, 1984, 167.
(b) Behr, L. C.; Fusco, R.; Jarobe, C. H. In Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles and Condensed
Rings; Wiley, R. H., Ed.; Wiley: New York, 1969, 28.
(11) (a) Porter, H. D.; Peterson, W. D. Org. Synth., Coll. Vol. 3
1955, 660. (b) Doyle, M. P.; Bryker, W. J. J. Org. Chem.
1974, 27, 1572. (c) Boulton, B. E.; Coller, B. A. W. Aust.
J. Chem. 1974, 27, 2343. (d) Suzuki, N.; Kaneko, Y.;
Nomoto, T.; Isawa, Y. J. Chem. Soc., Chem. Commun. 1984,
1523. (e) Doyle, M. P.; Siegfried, B.; Elliot, R. C.; Dellaria,
J. F. J. Org. Chem. 1977, 42, 2431.
(12) (a) Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Gschwend,
H. W.; Rodrigues, H. R. Org. React. (N. Y.) 1979, 26, 1.
(13) El Kazzouli, S.; Bouissane, L.; Khouili, M.; Guillaumet, G.
Tetrahedron Lett. 2005, 46, 6163.
(14) Beak, P.; Lee, B. J. Org. Chem. 1989, 54, 458.
(15) (a) Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687.
(b) Arbuzov, A. E. Chem. Zentr. 1906, II, 1639.
(16) Compound 22 (200g, 0.63 mol), Pd/C (10%, 20 g) in EtOH
(1 L) was sealed in an autoclave. The reaction proceeded
under H2 (50 psi) overnight. The solution was filtered
through Celite and concentrated. The residue was purified by
column chromatography to provide the aniline 23 (133 g,
73%). 1H NMR (400 MHz, CDCl3): d = 7.12–7.08 (m, 1 H),
7.07–6.95 (m, 1 H), 6.82–6.68 (m, 2 H), 4.19–3.99 (m, 2 H),
2.73–2.55 (m, 2 H), 2.51–2.41 (m, 2 H), 1.82–1.58 (m, 3 H),
1.47 (s, 9 H), 1.26–1.07 (m, 2 H). LCMS [MH+]: tR = 291.4,
1.81 min.
(17) To a solution of aniline 23 (763 g, 2.67 mol) in CH2Cl2
(10 L) was added NBS (935 g, 5.25 mol) portionwise. The
solution was stirred at r.t. until TLC indicated the reaction
was complete. The solvent was evaporated in vacuo and the
residue was re-dissolved in hexane–Et2O (4 L, 1:1). The
resulting solution was passed through a silica plug, washed
References and Notes
(1) (a) Roshak, A. K.; Callahan, J. F.; Blake, S. M. Curr. Opin.
Pharmacol. 2002, 2, 316. (b) Tak, P. P.; Firestein, G. S.
J. Clin. Invest. 2001, 107, 7. (c) Beg, A. A.; Baltimore, D.
Science 1996, 274, 782. (d) Foo, S. Y.; Nolan, G. P. Trends
Genet. 1999, 15, 229.
(2) Senftleben, U.; Karin, M. Crit. Care Med. 2002, 30, S18.
(3) (a) McIntyre, K. W.; Shuster, D. J.; Gillooly, K. M.;
Dambach, D. M.; Pattoli, M. A.; Lu, P.; Zhou, X. D.; Qiu,
Y.; Zusi, F. C.; Burke, J. R. Arthritis Rheum. 2003, 48,
2652. (b) Podolin, P. L.; Callahan, J. F.; Bolognese, B. J.; Li,
Y. H.; Carlson, K.; Davis, T. G.; Mellor, G. W.; Evans, C.;
Roshak, A. K. J. Pharmacol. Exp. Ther. 2005, 312, 373.
(4) Kerns, J. K.; Edwards, C. WO 2006002434, 2006.
(5) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(6) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org.
Chem. 2006, 71, 8166.
(7) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T.
J. Am. Chem. Soc. 1999, 121, 3539. (b) Uchiyama, M.;
Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.; Ohwada,
T.; Kondo, Y. J. Am. Chem. Soc. 2002, 124, 8514.
(8) Procedure for the Preparation of Compound 7
To a solution of tetramethylpiperidine (31.9 mL, 0.19 mol)
in THF (250 mL) at –20 °C was added n-BuLi in hexane (90
mL, 2.1 M, 0.19 mol) dropwise over 0.5 h. The reaction was
stirred at –10 °C for 1 h, and then cooled to –70 °C. Then,
Et2Zn (240 mL, 0.88 M in hexane, 0.21 mol) was added, and
the resulting solution was warmed to 0 °C over 0.5 h and
stirred at the temperature for 2 h. The solution was then
recooled to –70 °C. 2-Fluoro-5-bromobenzonitrile (36.7g,
0.18 mol) in THF (100 mL) was then added, and the
resulting solution was stirred at –70 °C for 0.5 h. The
reaction mixture was warmed to –30 °C and stirred for 5 h.
The solution was then re-cooled to –70 °C and iodine
Synlett 2008, No. 20, 3216–3220 © Thieme Stuttgart · New York

3220
X. Lin et al.
LETTER
began to fall. The reaction was warmed to r.t., and 5 L of
H2O were added. Then, NaOH (1 N) was added to adjust the
pH to 12. The layer was separated and the aqueous layer was
washed with Et2O. The resulting aqueous layer was heated to
90 °C until TLC indicated that conversion to the desired de-
Boc product was complete. The suspension was filtered out
though Celite pad. The filtrate was cooled to r.t. and HCl (1
N) solution was added to adjust the pH to 3–5. The
precipitate was filtered and dried over MgSO4. The desired
carboxylic acid 26 was obtained without further purification
(187 g, 71%). 1H NMR (400 MHz, CDCl3): d = 8.34 (d, 1 H,
J = 1.6 Hz), 8.17 (d, 1 H, J = 1.6 Hz), 4.42–4.36 (m, 2 H),
3.33–3.30 (m, 1 H), 3.01–2.86 (m, 2 H), 2.24–2.17 (m, 2 H),
2.02–1.87 (m, 2 H) 1.56 (s, 9 H). LCMS [MH+ – Boc]: tR =
324.2, 2.40 min. HRMS: m/z calcd for C18H22BrN3O4:
424.0872 [MH+]; found: 424.0863.
with hexane–Et2O mixture and concentrated to provide the
desired product 24 (1181 g, 98%). 1H NMR (400 MHz,
CDCl3): d = 7.44 (d, 1 H, J = 2.4 Hz), 7.04 (d, 1 H, J = 2.4
Hz), 4.30–4.00 (br m, 4 H), 2.67–2.61 (m, 2 H), 2.44–2.41
(m, 2 H), 1.73–1.61 (m, 3 H), 1.47 (s, 9 H), 1.20–1.16 (m,
2 H). LCMS [MH+ – Boc]: tR = 346.8, 2.97 min.
(18) To a solution of compound 24 (500 g, 1.12 mol) in 2.8 L of
AcOH (certified A.C.S. plus, Fisher) was added NaNO2
(2.26 mol, 97+%, Acros) portionwise at 20–30 °C. The
reaction mixture was stirred at r.t. for 30 min. The NaOH
solution was added to adjust the solution pH to 10, and the
solution was partitioned between EtOAc (4 L) and H2O (5.5
L). The layers were separated, and the aqueous phase was
extracted with EtOAc. The combined organic extracts were
washed with brine, dried over MgSO4, and evaporated. The
crude was filtered through a silica plug to provide the
cyclization product 25 as a brown-yellow solid (360 g, 70%).
The compound was used toward next step without further
purification. 1H NMR (400 MHz, CDCl3): d = 7.85 (d, 1 H,
J = 1.6 Hz), 7.66 (d, 1 H, J = 1.6 Hz), 4.34–4.18 (m, 2 H),
3.34–3.10 (m, 1 H), 3.02–2.88 (m, 2 H), 2.05–1.84 (m, 4 H),
1.51 (s, 9 H). LCMS [MH+]: tR = 457.8, 459.8, 2.64 min.
(19) Foster, R. H.; Leonhard, M. J. J. Org. Chem. 1979, 44, 4609.
(20) To a solution of indazole 25 (323 g, 0.703 mol) in 5.4 L of
CH2Cl2 were added Boc2O (242 mL, 1.06 mol), DMAP
(26.6 g, 0.218 mol), and Hünig’s base (133 mL). The
(21) To a suspension of acid 26 (187 g, 0.44 mol) in 3 L of
CH2Cl2 was added EDC·HCl (228 g, 1.19 mol) and
HOBt·H2O (80 g, 0.53 mol). After the reaction mixture
became clear, 240 mL of concentrated NH4OH was added
dropwise. The reaction mixture was stirred overnight at r.t.
The precipitate was filtered, washed with CH2Cl2, and H2O.
The resulting solid was stirred in a combination solution of
NaHCO3 and Na2CO3 for 2 h. The solid was filtered, washed
with H2O, and dried to provide the desired amide 4 (84 g,
45%). Extra product (69 g, 37%) was obtained by purifying
the filtrate with column chromatography (EtOAc–hexane).
1H NMR (400 MHz, CDCl3): d = 8.24 (d, 1 H, J = 1.6 Hz),
8.07 (d, 1 H, J = 1.6 Hz), 4.06–4.00 (m, 2 H), 3.33–3.30 (m,
1 H), 3.01–2.86 (m, 2 H), 1.99–1.89 (m, 2 H), 1.71–1.59 (m,
2 H), 1.43 (s, 9 H). LCMS [MH+]: tR = 423.0, 2.45 min.
HRMS: m/z calcd for C18H23BrN4O3: 423.1032 [MH+];
found: 423.1030.
resulting solution was stirred at r.t. overnight and purified by
filtering through silica plug to provide the N-1 Boc-protected
product (348 g, 88%). The product was used without further
purification. To a solution of N-Boc indazole (348 g, 0.622
mol) in 5 L anhyd Et2O at –78 °C was added 248 mL of n-
BuLi (2.5 M in hexanes, 0.62 mol) dropwise under N2. The
reaction mixture was stirred for 30 min at –78 °C, and CO2
was bubbled through until the temperature stop rising and
Synlett 2008, No. 20, 3216–3220 © Thieme Stuttgart · New York

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