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Stage #1: (S)-6-bromo-1-(1-(imidazo[1,2-a]pyridin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine hydrochloride; 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole With potassium carbonate In water; iso-butanol for 0.0833333h; Inert atmosphere;
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; palladium In water; iso-butanol at 30 - 65℃; for 2h; Inert atmosphere; |
5-6 Preparation of crude 3-GP S)-l -imidazoT 1.2-a1nyridin-6-ylcthyl1-5-t 1 -methylnyrazol-4- yl )triazolor4,5-b1nyrazine (la)
Under positive nitrogen pressure, a mixture of 5-bromo-3-[(lS)-l-imidazo[l,2-a]pyridin-6- ylethyl]triazolo[4,5-b]pyrazine hydrochloride (35g, 85.5mmol), l-methyl-4-(4,4,5,5- tetramethyl-l, 3, 2-dioxaborolan-2-yl)- lH-pyrazole (23.8g, 11 lmmol), potassium carbonate (29.6g, 2l4mmol), water (263mL) and butan-2-ol (438mL) is stirred for 5min. The mixture is then heated to 30°C and treated with Pd-l32 catalyst (0.6lg, 0.86mmol). The mixture is then stirred at 65°C for 2h. Upon completion, the resulting biphasic mixture is adjusted to 55°C and stirred with L- cysteine (7.77g, 64. lmmol), then stirred at 65°C for 6h. The stirring is then stopped and the mixture is allowed to settle. The aqueous phase is removed and the organic phase is treated with 14% w/w sodium chloride solution (35.0mL). The resulting mixture is stirred at 65°C for 30min, then stirring is stopped and the mixture is allowed to settle. The aqueous phase is removed and the organic phase is retained. The organic phase is diluted with anisole (l40mL) and stirred at 65°C. The mixture is filtered. The filtrate is treated with water (35mL) and the resulting mixture is stirred at 65°C for 30min. The stirring is then stopped and the mixture is allowed to settle. The aqueous phase is removed and the organic phase is dried azeotropically via distillation at atmospheric pressure. The mixture is concentrated to approximately 8 relative volumes. The temperature is adjusted to 90°C and further anisole (278mL) is added. The mixture is then stirred and azeotropically dried by distillation, with the mixture concentrated to approximately 10 relative volumes. The mixture is adjusted to 85°C and 3-[(lS)-l- imidazo[ 1 ,2-a]pyridin-6-ylethyl]-5-(l -methylpyrazol-4-yl)triazolo[4,5-b]pyrazine seed crystals (0.07g, 0.2mmol) are added. The mixture is stirred for lh, then cooled to 0°C, with stirring, over 8h. The mixture is stirred for a further 2h at 0°C before the mixture is filtered. The filter cake is washed twice with pre-cooled (<5°C) buan-2-ol (35mL) and then dried under vacuum ; Example 6 Preparation of 3-GP Si- 1 -imidazof 1.2-a1nyridin-6-ylcthyl1-5-f 1 -methylpyrazol-4- yl )triazolor4,5-b1pyrazine (I) A mixture crude 3-[(lS)-l-imidazo[l,2-a]pyridin-6-ylethyl]-5-(l-methylpyrazol-4- yl)triazolo[4,5-b]pyrazine (l08g, 0.3lmol), activated carbon (10.7g), ethanol (2850mL) and water (l50mL) is stirred at at least 76°C for 2h. The activated carbon is removed via filtration at >70°C, washing with ethanol (229mL) and The resulting mixture is passed through the wet mill for 75-80 theoretical passes and then stirred at 62°C for 6h. The mixture is then cooled to 0°C at a rate of 0.l°C/min and then stirred for 2h at 0°C. The mixture is then heated to 65°C at a rate of 0.35°C/min, and then stirred for 30min at 65°C. The mixture is then cooled to 0°C at a rate of 0. l4°C/min, and then stirred for 3h at 0°C. The mixture is then heated to 65°C at a rate of 0.35°C/min and then stirred for 30min at 65°C. The mixture is then cooled to 0°C at a rate of 0. l4°C/min and then stirred for 3h at 0°C. The wet mill is configured with the 6F+2P arrangement and set to a tip speed of 20.5 m/s with the wet mill jacket cooling engaged to cool the mill to 0°C prior to the start of milling. The mixture is passed through the wet mill for 80-90 theoretical passes at 0°C. The mixture is then heated to 65°C at a rate of 0.35°C/min, and then stirred for 30min at 65°C. The mixture is then cooled to 0°C at a rate of 0. l4°C/min, and then stirred for 3h at 0°C. The mixture is then heated to 65°C at a rate of 0.35°C/min, and then stirred for 30min at 65°C. The mixture is then cooled to 0°C at a rate of 0.l4°C/min, and then stirred for 3-5h at 0°C. The mixture is then filtered, and the wet cake washed with pre-cooled (< 5°C) ethanol (2l4mL). The cake is dried to constant weight in a vacuum oven at 45-55°C to give 3- [(lS)-l-imidazo[l,2-a]pyridin-6-ylethyl]-5-(l-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine as an off-white coloured solid. The material is de-lumped through a 2mm screen mp 205.9 - 208.8 °C; 1H NMR (400 MHz, DMSO-de) d = 9.19 (s, 1H), 8.83 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.62 - 7.55 (m, 2H), 7.42 (dd, J= 1.7, 9.4 Hz, 1H), 6.45 (q, J= l. Hz, 1H), 3.98 (s, 3H), 2.22 (d, J= l. Hz, 3H); 13C NMR (DMSO-de, 101 MHz): d = 147.9, 147.2, 143.9, 141.9, 138.5, 137.4, 133.7, 131.6, 125.4, 124.3, 123.9, 119.4, 117.1, 113.8, 55.5, 40.1, 39.1, 19.6 ppm; HRMS (ESI/Q-ToF) m/z: [M+H-N2]+ Calculated for Ci7Hi6N7 318.1462; Found 318.1486. |
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