With ammonia; hydrogen In methanol at 20℃; for 6 h;
A mixture of 1-tosyl-1 H-indole-4-carbonitrile (0.5 g, 1.69 mmol), 5percent NH3 in methanol (5.0 mL) and Raney Nickel (0.2 g) in methanol (15.0 ml) was hydrogenated at 5 Torr for 6 h at it After completion of the reaction, the Raney Nickel was filtered off through a pad of celite under vacuum and washed with methanol (5 x 2 mL). The combined filtrates were evaporated to dryness under reduced pressure. The residue was washed with 10 percent diethyl ether in pentane to yield the title compound as a white solid (0.45 g, 78 percent). [1H-NMR (CDCI3, 300 MHz): δ 7.72-7.59 (m, 3H), 7.44-7.52 (m, 1 H), 7.33-6.72 (m, 5 H), 4.12-4.01 (m, 2H), 2.27 (s, 3H)].
step 3: To a solution of 44 (620 mg, 2 mmol) in EtOH (15 mL) was added zinc powder (320 mg, 5.0 mmol) and NH4C1 (0.53 g, 10 mmol). The reaction mixture was heated at reflux overnight, filtered and the filtrate was concentrated to dryness. The residue was diluted with DCM (100 mL) and water (20 mL). The organic layer was separated, dried (MgSO i), filtered and concentrated to afford 600 mg (100percent) of (1- tosyl-lH-indol-4-yl)methanamine (46) as yellow syrup: MS (ESI) m/z = 284.1 [M-15] +.
In toluene; for 16.0h;Reflux;Product distribution / selectivity;
To a stirred mixture of 1-Boc-piperidin-4-one (0.25 g, 1.256 mmol), 4 A molecular sieves (0.25 g), allyl boronic acid pinacol ester (0.255 g, 1.507 mmol) in toluene (10.0 mL), 1-tosyl- 1 H-indol-4-yl)methanamine (0.45 g, 1.507 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (eluent: 10% ethyl acetate in hexane) to yield the title compound as a white solid (0.2 g, 70 %). LCMS RtA = 0.341 , [M+H]+ = 524.0
70%
In toluene; for 16.0h;Reflux; Molecular sieve;
Example 31-((1H-indol-4-yl)methyl)-9-(4,6-dimethylpyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one a) tert-butyl 4-allyl-4-((1-tosyl-1H-indol-4-yl)methylamino)piperidine-1-carboxylate; To a stirred mixture of 1-Boc-piperidin-4-one (0.25 g, 1.256 mmol), 4 molecular sieves (0.25 g), allyl boronic acid pinacol ester (0.255 g, 1.507 mmol) in toluene (10.0 mL), 1-tosyl-1H-indol-4-yl)methanamine (0.45 g, 1.507 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (eluent: 10% ethyl acetate in hexane) to yield the title compound as a white solid (0.2 g, 70%). [LCMS RtE=0.341, [M+H]+=524.0]
70%
In toluene; for 16.0h;Reflux; Molecular sieve;
Example 3: 1-U1H-indol-4-vhmethvn-9-f4.6-dimethylpyrimidin-2-yl)-1,9- diazaspiror5.51undecan-2-onea) tert-butyl 4-allyl-4-((1-tosvH H-indol-4-yl)methylamino)piperidine-1-carboxylateTo a stirred mixture of 1-Boc-piperidin-4-one (0.25 g, 1.256 mmol), 4 A molecular sieves (0.25 g), allyl boronic acid pinacol ester (0.255 g, 1.507 mmol) in toluene (10.0 mL), 1-tosyl- 1H-indol-4-yl)methanamine (0.45 g, 1.507 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (eluent: 10% ethyl acetate in hexane) to yield the title compound as a white solid (0.2 g, 70%). [LCMS RtE = 0.341 , [M+H]+ = 524.0]
With ammonia; hydrogen;Raney Nickel; In methanol; at 20.0℃; under 5.0 Torr; for 6.0h;
A mixture of 1-tosyl-1 H-indole-4-carbonitrile (0.5 g, 1.69 mmol), 5% NH3 in methanol (5.0 mL) and Raney Nickel (0.2 g) in methanol (15.0 ml) was hydrogenated at 5 Torr for 6 h at it After completion of the reaction, the Raney Nickel was filtered off through a pad of celite under vacuum and washed with methanol (5 x 2 mL). The combined filtrates were evaporated to dryness under reduced pressure. The residue was washed with 10 % diethyl ether in pentane to yield the title compound as a white solid (0.45 g, 78 %). [1H-NMR (CDCI3, 300 MHz): delta 7.72-7.59 (m, 3H), 7.44-7.52 (m, 1 H), 7.33-6.72 (m, 5 H), 4.12-4.01 (m, 2H), 2.27 (s, 3H)].
step 3: To a solution of 44 (620 mg, 2 mmol) in EtOH (15 mL) was added zinc powder (320 mg, 5.0 mmol) and NH4C1 (0.53 g, 10 mmol). The reaction mixture was heated at reflux overnight, filtered and the filtrate was concentrated to dryness. The residue was diluted with DCM (100 mL) and water (20 mL). The organic layer was separated, dried (MgSO i), filtered and concentrated to afford 600 mg (100%) of (1- tosyl-lH-indol-4-yl)methanamine (46) as yellow syrup: MS (ESI) m/z = 284.1 [M-15] +.
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120.0℃;Sealed tube;
step 4: A tube was charged with 53 (415 mg, 1.38 mmol), 46 (486 mg, 2.07 mmol), DIPEA (1.0 ml) and IPA (3 mL), degassed, sealed and heated at 120 C overnight. The mixture was concentrated in vacuo. The residue was purified by Si02 chromatography eluting with a DCM/MeOH gradient (3.3 to 5%> MeOH) to afford 330 mg (48%) of N4-(5-cyclopropyl-lH-pyrazol-3-yl)- N2-((l-tosyl-lH-indol-4-yl) methyl) pyrimidine-2,4-diamine (50) as yellow solid: MS (ESI) m/z = 500.3 [M+l] +.
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