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Synlett

Volumn , Issue 20, 2008, Pages 3216-3220

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

(6) Lin, Xichen a Busch Petersen, Jakob a Deng, Jianghe a Edwards, Christine b Zhang, Zhaoguo c Kerns, Jeffrey K a

a GLAXOSMITHKLINE (United States)

b Argenta Discovery Ltd (United Kingdom)

c SHANGHAI JIAO TONG UNIVERSITY (China)

Author keywords

Cyclization; IKK2 inhibitors; Indazole; Lithiation; Organometallic reagents

Indexed keywords

EID: 58149355914 PISSN: 09365214 EISSN: None Source Type: Journal
DOI: 10.1055/s-0028-1087364 Document Type: Article

Times cited : (8)

References (33)

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13
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- 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
- 3): δ = 8.13 (dd, 1 H, J = 4.8, 2.0 Hz), 7.74 (dd, 1 H, J = 4.8, 2.0 Hz).

14
- 58149361135
- 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 CeCl 3 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 EtO
- 3): 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).

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28
- 58149358672
- R = 291.4, 1.81 min.
- R = 291.4, 1.81 min.

29
- 58149341063
- To a solution of aniline 23 (763 g, 2.67 mol) in CH 2Cl2 (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, tR, 346.8, 2.97 min
- R = 346.8, 2.97 min.

30
- 58149341974
- 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, Acres) 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
- R = 457.8, 459.8, 2.64 min.

31
- 0018577882
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- Foster, R.H.¹ Leonhard, M.J.²

32
- 58149361153
- 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 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
- +]; found: 424.0863.

33
- 58149332082
- To a suspension of acid 26 (187 g, 0.44 mol) in 3 L of CH 2Cl2 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 Na2CO 3 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
- +]; found: 423.1030.

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