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Stage #1: at -40℃; for 1 h; Stage #2: With ammonium chloride In tetrahydrofuran; water
At -40°C, vinylmagnesium bromide (300mL of 1.0M solution in THF, 300mmol) was added dropwise to a solution of 3-nitro-4-fluoro-bromobenzene (22 g, 100mmol) in THF (700ml_). After 1 h at -40°C, the mixture was quenched by aqueous NH4CI solution and extracted by EtOAc. The organic layer was dried over Na2S04 and concentrated to give the crude product which was purified by silica gel column chromatography affording 4- bromo-7-fluoro-1 H-indole (5 g, 23.3percent). 1H NMR CDCI3400 MHz δ 6.56-6.58 (m, 1 H), 6.72-6.79 (m, 1 H), 7.06-7.17 (m, 1 H), 7.20-7.24 (m, 1 H), 8.45 (s, 1 H).
23.3%
at -40℃; for 1 h;
At -40° C., vinylmagnesium bromide (300 mL of 1.0M solution in THF, 300 mmol) was added dropwise to a solution of 3-nitro-4-fluoro-bromobenzene (22 g, 100 mmol) in THF (700 mL). After 1 h at -40° C., the mixture was quenched by aqueous NH4Cl solution and extracted by EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column chromatography affording 4-bromo-7-fluoro-1H-indole (5 g, 23.3percent). 1H NMR CDCl3400 MHz δ 6.56-6.58 (m, 1H), 6.72-6.79 (m, 1H), 7.06-7.17 (m, 1H), 7.20-7.24 (m, 1H), 8.45 (s, 1H).
22%
at -40℃; for 1 h;
At -40 °C, vinylmagnesium bromide (75 mmol) in tetrahydrofuran (75 mL) was added dropwise, in the course of 30 min, to a solution of 4-bromo-1-fluoro-2-nitrobenzene (5.5 g, 25 mmol) in tetrahydrofuran (100 mL). After 1 h at -40 °C, the mixture was poured into a saturated aqueous solution (50 mL) of ammonium chloride. The organic layer was evaporated. The crude was submitted to flash chromatography through silica gel to obtain 1.2 g (22percent yield) of 4-bromo-7-fluoro-1H-indole.
22%
at -40℃; for 1.5 h;
a) 2-(Bromomethyl)-4-chloro-1 -(4-chloro-2-fluorophenethyl)benzeneAt -40 °C, vinylmagnesium bromide (75 mmol) in tetrahydrofuran (75 ml_) was added dropwise. in the course of 30 min, to a solution of 4-bromo-1 -fluoro-2- nitrobenzene (5.5 g, 25 mmol) in tetrahydrofuran (100 ml_). After 1 h at -40 °C, the mixture was poured into a saturated aqueous solution (50 ml_) of ammonium chloride. The organic layer was evaporated. The crude was submitted to flash chromatography through silica gel to obtain 1 .2 g (22percent yield) of 4-bromo-7-fluoro- 1 H-indole.
12%
at -40℃; for 1.5 h; Inert atmosphere
Example 11 N4 -(5-cyclopropyl-lH-pyrazol-3-yl)- N2 -((7-fluoro-lH-indol-4-yl)methyl)pyrimidine-2,4-diamine (1-47) step 1 : To a solution of 4-bromo-l -fluoro-2-nitrobenzene (1.1 g, 5.0 mmol) in THF (20 mL) at -40 °C under nitrogen atmosphere was added slowly vinylmagnesium bromide (1 M in THF, 15.5 mL, 15.5 mmol). The reaction mixture was stirred for 1.5 h then quenched with saturated NH4C1 aqueous solution (10 mL). The mixture was partitioned between EtO Ac (300 mL) and water (50 mL). The organic layer was separated, washed with brine, dried (MgS04), filtered and evaporated in vacuo. The residue was purified by S1O2 chromatography eluting with 2.5percent EtO Ac/petroleum ether to afford 0.125 g (12percent) of 4- bromo-7-fluoro-lH-indole (110) as brown oil: MS (ESI) m/z = 214 [M-l] +.
580 mg
at -78 - -40℃; for 1.66 h;
To 2.42 g of 3-bromo-6-fluoronitrobenzene (B9.1) in -30 mL THF at -78°C was added 37 mL 1.0 M vinylmagnesium bromide (in THF). The reaction was stirred at -78°C for 10 minutes and then at -40°C for 1.5 hours. The reaction mixture was quenched with saturated NH4CI. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organics were washed with brine and concentrated. The residue was dissolved in DCM and an Isco silica column was run utilizing 100percent DCM. Overall, 580 mg B9.2 was obtained. This indole intermediate was alkylated with Mel utilizing analogous procedures as described in Scheme 8. Once B9.3 was in hand, it was reacted with H2NBoc in dioxane, with Pd2(dba)3, Xantphos, and Cs2C03. The reaction mixture was stirred under an argon atmosphere at reflux overnight. The reaction was cooled and dioxane was removed in vacuo. The resulting solid was suspended in DCM and filtered. The filtrate was partitioned with water and the organic layer was removed and concentrated. This resulted in a residue which was treated with 4.0 N HCI in dioxane (excess). The reaction was stirred for 2 hours and then concentrated to give B9.4 which was utilized instead of 5-aminoindazole (Scheme 1). Additionally a Cbz- deprotection utilizing BBr3 in DCM (Scheme 7, example 82) was undertaken to give the title compound. MS found for C18H20F3N7O as (M+H)+408.3.
Reference：
[1] European Journal of Organic Chemistry, 2006, # 13, p. 2956 - 2969
[2] Patent: WO2013/117522, 2013, A1, . Location in patent: Page/Page column 39
[3] Patent: US2015/18367, 2015, A1, . Location in patent: Paragraph 0173; 0174
[4] Patent: EP2570125, 2013, A1, . Location in patent: Paragraph 0151
[5] Patent: WO2013/37960, 2013, A1, . Location in patent: Page/Page column 74
[6] Patent: WO2013/26914, 2013, A1, . Location in patent: Page/Page column 135
[7] Patent: WO2013/78468, 2013, A1, . Location in patent: Paragraph 0526; 0527
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