Efficient and Scalable Synthesis of 3,5,7-Trisubstituted 1H-Indazoles as Potent IKK2 Inhibitors

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

References and Notes

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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
(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).

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): 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).

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): 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.

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 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.

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): 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.

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 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.

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): 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.