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With hydrazine In tetrahydrofuran; methanol; water at 20℃; for 5 h;
To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H20, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 0C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 percent). NMR δH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).
37%
With hydrazine In tetrahydrofuran; methanol; water at 0 - 20℃; for 5 h;
Reference Example 44-Bromo-6-fluoro-lH-indoleTo a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) was added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 °C. The mixture was cooled to RT and evaporated to dryness to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue (10.0 g, theoretical yield). To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H2O, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 0C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 percent).NMR δH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).
Stage #1: at 20℃; Heating / reflux Stage #2: With iron; acetic acid In N,N-dimethyl-formamide for 0.666667 h; Heating / reflux Stage #3: With water; sodium carbonate In dichloromethane
Intermediate 35; 4-Bromo-6-fluoro-lH-indole; l-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and(dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refiuxed under N2 for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refiuxed for 40 min., partitioned between DCM and saturated aq. Na2CO3/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39percent) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.
27%
Stage #1: With pyrrolidine In 1,4-dioxane at 20 - 100℃; for 18 h; Stage #2: With iron; acetic acid In 1,4-dioxane for 1 h; Reflux
Example 41 N4-(5-Cyclobutyl- 1 H-pyrazol-3-yl)-N2-((6-fluoro- 1 H-indol-4-yl)methyl)pyrimidine-2,4-diamine Formate (1-88) step 1 : To a solution of l-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100 °C for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50percent aq. NaOH and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (MgSO i), filtered and concentrated in vacuo. The residue was purified by Si02 chromatography eluting with an EtO Ac/petroleum ether gradient (5 to 30percent EtOAc) to afford 1.16 g (27percent) of 4-bromo-6-fluoro-lH-indole (224) -as brown solid: MS (ESI) m/z = 213.9 [M+l] +.
An acetic acid (20 ml) solution containing the deep brown oily matter obtained in the 2nd step was added to amixture of iron powder (3.61 g) and acetic acid (20 ml) at 110°C for 30 minutes. The resulting mixture was stirred for 1hour and then diluted with ethyl acetate. Insoluble matter was removed by filtration with Celite, the filtrate was washedwith water and 1M hydrochloric acid (x3). The obtained organic layer was poured into a saturated aqueous sodiumhydrogen carbonate solution to separate the organic layer, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Thereafter, activated carbon was added and insoluble matter wasremoved by filtration with Celite. The solvent was distilled away under reduced pressure, and light brown oily matter of4-bromo-6-fluoro-1H-indole (880 mg) was thus obtained.MS (ESI m/z): 214, 216 (M+H)RT (min): 1.561H-NMR (DMSO-d6, 300MHz) δ:11.53 (br, 1H), 7.46 (t, 1H, J = 3.0Hz), 7.24 (dd, 1H, J = 5.6, 3.0 Hz), 7.19 (dd, 1H, J =9.2, 2.0Hz), 6.39 (d, 1H, J = 2.0Hz)
With hydrazine;Raney- Nickel; In tetrahydrofuran; methanol; water; for 24h;Product distribution / selectivity;
To a solution of crude l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-vinyl]- pyrrolidine (2.74 g) in tetrahydrofuran (25 ml) and methanol (25 ml) was added Raney nickel, 50% slurry in water, active catalyst (5.0 ml) followed by careful addition of hydrazine monohydrate (0.63 ml). After stirring for 24 hours the reaction mixture was filtered through celite and the filtrate reduced in vacuo. The residue was purified by flash chromatography to give 4-bromo-6-fluoro-l H-indole (0.80 g).
An acetic acid (20 ml) solution containing the deep brown oily matter obtained in the 2nd step was added to amixture of iron powder (3.61 g) and acetic acid (20 ml) at 110°C for 30 minutes. The resulting mixture was stirred for 1hour and then diluted with ethyl acetate. Insoluble matter was removed by filtration with Celite, the filtrate was washedwith water and 1M hydrochloric acid (x3). The obtained organic layer was poured into a saturated aqueous sodiumhydrogen carbonate solution to separate the organic layer, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Thereafter, activated carbon was added and insoluble matter wasremoved by filtration with Celite. The solvent was distilled away under reduced pressure, and light brown oily matter of4-bromo-6-fluoro-1H-indole (880 mg) was thus obtained.MS (ESI m/z): 214, 216 (M+H)RT (min): 1.561H-NMR (DMSO-d6, 300MHz) delta:11.53 (br, 1H), 7.46 (t, 1H, J = 3.0Hz), 7.24 (dd, 1H, J = 5.6, 3.0 Hz), 7.19 (dd, 1H, J =9.2, 2.0Hz), 6.39 (d, 1H, J = 2.0Hz)
With hydrazine;Raney.(R).- Nickel; In tetrahydrofuran; methanol; water; at 0 - 20℃; for 0.666667h;Product distribution / selectivity;
Reference Example 14; 4-Bromo-6-fluoro-ll?~indoIe; Prepared according to the method used in the preparation of 4-bromo-lT- indole-6-sulfonic acid dimethylamide using l-bromo-5-fluoro-2-methyl-3-nitro- benzene in place of 3-bromo-4-iV,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (6.06 g, 33 percent).NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.I5 IH), 7.12 (dd, J = 2.1, 9.1, IH)5 7.20-7.25 (m, IH) and 8.25 (s, IH).
Intermediate 35; 4-Bromo-6-fluoro-lH-indole; l-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and(dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refiuxed under N2 for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refiuxed for 40 min., partitioned between DCM and saturated aq. Na2CO3/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39percent) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.
27%
Example 41 N4-(5-Cyclobutyl- 1 H-pyrazol-3-yl)-N2-((6-fluoro- 1 H-indol-4-yl)methyl)pyrimidine-2,4-diamine Formate (1-88) step 1 : To a solution of l-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100 °C for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50percent aq. NaOH and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (MgSO i), filtered and concentrated in vacuo. The residue was purified by Si02 chromatography eluting with an EtO Ac/petroleum ether gradient (5 to 30percent EtOAc) to afford 1.16 g (27percent) of 4-bromo-6-fluoro-lH-indole (224) -as brown solid: MS (ESI) m/z = 213.9 [M+l] +.
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; for 1h;
Intermediate 36; 4-Bromo-6-fluoro-l-(phenylsulfonyl)-lH-indole; Aq. 4 M NaOH (5 mL) was added to a stirring mixture of 4-bromo-6-fluoro-lH-indole (500 mg, 2.34 mmol; Intermediate 35), benzenesulfonyl chloride (329 muL g, 2.57 mmol) and tetrabutylammonium hydrogen sulfate (78 mg, 0.23 mmol) in DCM (30 mL). The reaction mixture was stirred Ih, combined with an earlier batch of this intermediate (followed this experimental and starting with 4-bromo-6-fluoro-lH-indole, 152 mg, 0.71 mmol; Intermediate 35), washed twice with water, dried and concentrated. The product <n="93"/>(1.08 g, 100percent) was obtained as a beige solid. MS (ESI+) for Ci4H9BrFNO2S m/z 354 (M+H)+.
79%
With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 4h;Inert atmosphere;
To a solution of 4-bromo-6-fluoro-indole (2 g, 9.38 mmol) in anhydrous tetrahydrofuran (30 mL) cooled in an ice bath was added sodium hydride (0.452 g, 11.3 mmol, 60percent in mineral oil). The reaction mixture was stirred under nitrogen for 10 min before benzenesulfonyl chloride (1.44 mL, 11.3 mmol) was added. The black solution was allowed to warm to room temperature over 4 h. TLC and LCMS indicated completion of the reaction. Saturated aqueous ammonium chloride solution was added slowly, and the resulting solution was extracted with ethyl acetate (2*). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude solid was triturated with ethanol. The resulting beige solid was collected by filtration to give 4-bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole (2.6 g, 79percent yield).
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