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DOI: 10.1055/s-0028-1087364
Efficient and Scalable Synthesis of 3,5,7-Trisubstituted 1H-Indazoles as Potent IKK2 Inhibitors
Publication History
Publication Date:
24 November 2008 (online)
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Abstract
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-trisubstituted 1H-indazole, which was identified as a potent IKK2 inhibitor. The sequence allows for a scalable preparation of the target compound in eight steps and proceeds in 40% overall yield from readily available starting material.
Key words
cyclization - IKK2 inhibitors - indazole - lithiation - organometallic reagents
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References and Notes
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
(162.6 g, 0.63 mol) in THF (300 mL) was added.
The 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): δ = 8.13 (dd,
1 H, J = 4.8,
2.0 Hz), 7.74 (dd, 1 H, J = 4.8,
2.0 Hz).
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): δ = 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).
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): δ = 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+]: t R = 291.4, 1.81 min.
17To 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 with hexane-Et2O
mixture and concentrated to provide the desired product 24 (1181 g, 98%). ¹H
NMR (400 MHz, CDCl3): δ = 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]: t
R = 346.8, 2.97
min.
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): δ = 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+]: t R = 457.8, 459.8, 2.64 min.
20To 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 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 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): δ = 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]: t R = 324.2, 2.40 min. HRMS: m/z calcd for C18H22BrN3O4: 424.0872 [MH+]; found: 424.0863.
21To 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): δ = 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+]: t R = 423.0, 2.45 min. HRMS: m/z calcd for C18H23BrN4O3: 423.1032 [MH+]; found: 423.1030.