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With N,N-dimethyl-formamide; trichlorophosphate In acetonitrile at 55℃; for 0.5 h;
POCl3 (0.08 ml, 0.90 mmol) was added to Intermediate I (37 mg, 0.18 mmol) dissolved in 0.78 mL of acetonitrile. A drop of DMF was added and the reaction mixture was stirred at 55 °C for 30 minutes. The reaction mixture was then concentrated in vacuo and the resultant solid was dissolved in 2 M ammonia in methanol followed by concentrating this solution in vacuo. The resultant solid was dissolved in a minimal amount of water and the product was extracted into dichloromethane (4X). The organic layers were combined and washed with saturated NaHC03, (IX), concentrated in vacuo, and dried over Na2S04. Concentration of the solution afforded 33 mg (98percent yield) of Intermediate J. .H-NMR (300 MHz, CDC13) δ 1.46 (d, 6H, J = 6.9 Hz), 3.29-3.38 (m, 1H), 7.33 (d, 1H, J = 4.8 Hz), 7.61 (d, 1H, J= 5.1 Hz), 7.82 (s, 1H). MS (ESI) (M+H)+ 196
With N-iodo-succinimide In N,N-dimethyl-formamide at 60℃; for 3 h;
Intermediate J (33 mg, 0.17 mmol) dissolved in 0.18 mL of DMF was added to NIS (39 mg, 0.17 mmol) dissolved in 0.6 mL of DMF. The reaction mixture was heated to 60 °C for 3 h and then cooled to room temperature. The reaction mixture was partitioned between 1 M a2S03 and dichloromethane. The aqueous layer was then extracted with dichloromethane (3X). The organic layers were combined, dried over a2S04 and concentrated in vacuo to afford 34 mg (62percent yield) of pure Intermediate K. .H-NMR (300 MHz, CDC13) δ 1.41 (d, 6H, / = 6.9 Hz), 3.20-3.31 (m, 1H), 7.28 (d, 1H, J= 5.1 Hz), 7.65 (d, 1H, J = 5.1 Hz). MS (ESI) (M+H)+ 322.1.
With N,N-dimethyl-formamide; trichlorophosphate; In acetonitrile; at 55℃; for 0.5h;
POCl3 (0.08 ml, 0.90 mmol) was added to Intermediate I (37 mg, 0.18 mmol) dissolved in 0.78 mL of acetonitrile. A drop of DMF was added and the reaction mixture was stirred at 55 C for 30 minutes. The reaction mixture was then concentrated in vacuo and the resultant solid was dissolved in 2 M ammonia in methanol followed by concentrating this solution in vacuo. The resultant solid was dissolved in a minimal amount of water and the product was extracted into dichloromethane (4X). The organic layers were combined and washed with saturated NaHC03, (IX), concentrated in vacuo, and dried over Na2S04. Concentration of the solution afforded 33 mg (98% yield) of Intermediate J. .H-NMR (300 MHz, CDC13) delta 1.46 (d, 6H, J = 6.9 Hz), 3.29-3.38 (m, 1H), 7.33 (d, 1H, J = 4.8 Hz), 7.61 (d, 1H, J= 5.1 Hz), 7.82 (s, 1H). MS (ESI) (M+H)+ 196
With trichlorophosphate; In ethyl acetate; N,N-dimethyl-formamide; at 0 - 20℃; for 0.75h;
To a solution of Intermediate 5-c (2.5 g, 11.7 mmol) in ethyl acetate (36.6 ml) cooled to 0C was added DMF (2.4 ml) and phosphorous oxychloride (1.9 ml, 21.0 mmol) dropwise. After the addition was completed, the reaction mixture was stirred for 45 minutes at room temperature. An ice cooled saturated aqueous solution of Na2CO3 and dichloromethane were slowly added, the organic layer was separated, the aqueous phase was extracted twice with dichioromethane, the combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide Intermediate 5-d as a beige oil.
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 60.0℃; for 3.0h;
Intermediate J (33 mg, 0.17 mmol) dissolved in 0.18 mL of DMF was added to NIS (39 mg, 0.17 mmol) dissolved in 0.6 mL of DMF. The reaction mixture was heated to 60 C for 3 h and then cooled to room temperature. The reaction mixture was partitioned between 1 M a2S03 and dichloromethane. The aqueous layer was then extracted with dichloromethane (3X). The organic layers were combined, dried over a2S04 and concentrated in vacuo to afford 34 mg (62% yield) of pure Intermediate K. .H-NMR (300 MHz, CDC13) delta 1.41 (d, 6H, / = 6.9 Hz), 3.20-3.31 (m, 1H), 7.28 (d, 1H, J= 5.1 Hz), 7.65 (d, 1H, J = 5.1 Hz). MS (ESI) (M+H)+ 322.1.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 0.25h;Inert atmosphere;
To a solution of Intermediate 5-c (1.9 g, 9.7 mmol) in DMF cooled to 0C was slowly added a 0.7N solution of N-bromosuccinimide in DMF (15.2 ml, 10.7 mmol) under an atmosphere of nitrogen. After the addition was completed the reaction mixture was stirred for 15 minutes. Water was added; a precipitate formed, and was collected by filtration to provide Intermediate 5-e as a beige solid.
3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine[ No CAS ]
N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide[ No CAS ]
8-chloro-5-iodo-3-isopropylimidazo[1,5-a]pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
To a stirred solution of 8-chloro-3-isopropylimidazo[i,5-ajpyrazine (31 g, 158.5 mmol) indry THF (300 mL) at -78 C under nitrogen was added n-butyllithium (2.5 M in hexanes,82.4 mL, 206 mmol), keeping the internal temperature below -65 C. After stirring for 30 mma solution of iodine (56.3 g, 221.8 mmol) in THF (50 mL) was added dropwise over 10 mmkeeping the internal temperature below -65 C during addition. The resulting suspension wasstirred for 1 hour whilst warming to -10 C then the reaction mixture was quenched by theaddition of saturated aqueous NH4C1 and extracted with 2-methyltetrahydrofuran (x3). The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by passage through a silica-gel pad, eluting with 0-20% EtOAc in DCM to give an orange solid, which was triturated with Et20 to givethe title compound 5B as a yellow solid (41.2 g, 81%). LC-MS: Rt = 1.29 mm, m/z = 322.0[M+Hj +
methyl 2-(4-(8-amino-5-(4-((tert-butoxycarbonyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)acetate[ No CAS ]
tert-butyl (4-(8-amino-3-isopropyl-1-(4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)naphthalen-1-yl)imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate[ No CAS ]
tert-butyl (4-(8-amino-3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate[ No CAS ]
tert-butyl (4-(8-amino-3-isopropyl-1-(4-((5-phenyl-1H-imidazol-2-yl)methyl)naphthalen-1-yl)imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate[ No CAS ]
tert-butyl (4-(8-amino-1-(4-(((2-chlorophenyl)methyl)sulfonamido)-3-fluorophenyl)-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate[ No CAS ]
8-chloro-3-isopropylimidazo[1,5-a]pyrazine-5-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
To a solution of 8-chloro-3-isopropylimidazo[1,5-ajpyrazine 3A (1.00 g, 5.11 mmol) in THFat -65 C was added dropwise a solution of n-butyllithium (2.5 M solution in THF, 2.9 mL,7.16 mmol), keeping the temperature below -55 C. The resulting dark brown solution was stirred at -78 C for 1 h then ethyl formate (0.62 mL, 7.67 mmol) was added dropwise and the mixture was stirred at -78 C for 1.5 h. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated invacuo. The residue was purified by silica-gel chromatography, eluting with 0-50% EtOAc in isohexane to give the title compound 3B as a yellow oil that crystallised on standing (900 mg, 79%). LC-MS (Method 1): Rt = 1.06 mm, m/z = 224.1 [M(35C1)+Hf?.
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