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cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium 3-carboxy-2,3-dihydroxy-propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Example 5: c/s-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1 -(2-phenyl-quinolin-7-yl)- imidazo[1 ,5-a]pyrazin-7-ium 3-carboxy-2,3-dihydroxy-propionateThis material was prepared by heating <strong>[867160-71-2]OSI-906</strong> with a slight excess of L-tartaric acid in ethanol and then allowing the mixture to cool. The solid was collected by filtration and dried. The DSC, XRPD, and 1H NMR (300MHz, DMSO-d6) of the sample were recorded and are reproduced in Figs. 4, 5, and 6, respectively
cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium 3-carboxy-acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Example 7: c/s-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1 -(2-phenyl-quinolin-7-yl)- imidazo[1 ,5-a]pyrazin-7-ium 3-carboxy-acrylateThis material was prepared by heating <strong>[867160-71-2]OSI-906</strong> with a slight excess of fumaric acid in ethanol/ water and then allowing the mixture to cool. The solid was collected by filtration and dried. The DSC, XRPD, and 1H NMR (300MHz, DMSO-d6) of the sample were recorded and are reproduced in Figs. 10, 1 1 , and 12, respectively
Example 8: c/s-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1 -(2-phenyl-quinolin-7-yl)- imidazo[1 ,5-a]pyrazin-7-ium methanesulfonate O- HOThis material was prepared by heating <strong>[867160-71-2]OSI-906</strong> with a slight excess of methane sulfonic acid in 2-propanol and then allowing the mixture to cool. The solid was collected by filtration and dried. The DSC, XRPD, and 1H NMR (300MHz, DMSO-d6) of the sample were recorded and are reproduced in Figs. 13, 14, and 15, respectively.
EXAMPLESExample 1 : c/s-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1- methylcyclobutanol (OSI-906) (Compound 1 ):A vessel was charged with DMF (79 kg), c/s-3-(8-amino-1-bromo-imidazo[1 ,5-a]pyrazin- 3-yl)-1 -methylcyclobutanol (16.725 kg), 2-phenyl-7-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)-quinoline (22.4 kg), triphenylphosphine (0.586 kg), cesium carbonate (36.7 kg) and water (20.1 kg). The reaction mixture was degassed and heated to 95-105 C and a solution of palladium acetate (0.125 kg) in DMF (9.8 kg) was added and rinsed in with DMF (5.9 kg). After the reaction was complete, water (154 kg) was added keeping the temperature above 70 C. The resultant slurry was cooled and the solid was collected by filtration. After washing with a mixture of DMF (9.4 kg) and water (23.4 kg) and then water (67 kg) the solid was suspended in water (167 kg) at 50 C and the pH of the mixture was adjusted to 2.9 with 6N hydrochloric acid (10.9 kg). The resultant yellow slurry was filtered to remove the major impurities and the cake was washed with water (67 kg). The acid solution was stirred at 50-55 C and polymer bound trimercaptotriazine resin (MP-TMT) (4.9 kg) was added. The mixture was stirred for 23 hours, the resin was removed by filtration and the cake was washed with water (58 kg).The resultant acid solution was diluted with 2-propanol (82 kg), the temperature was adjusted to 35-45 C and the pH was adjusted to 5.0 by the addition of 1 N sodium hydroxide solution. The mixture was cooled, the yellow product was collected by filtration and was washed with water (33 kg). The solid was re-suspended in water (157 kg) stirred, filtered and washed with water (125 kg). The solid was dried under vacuum at 45-55 C (the resulting material was a hemihydrate of OSI-906 designated Form C) and was then stirred in refluxing 2- propanol (157 kg) for 3 hours. The mixture was cooled and the solid was isolated by filtration. After washing with 2-propanol (26.7 kg), the product was dried at 45-55 C under vacuum to yield 15.6 kg (65% yield) of OSI-906. The resulting material was an anhydrous crystalline form of OSI-906 designated Form A
EXAMPLESExample 1 : c/s-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1 ,5-a]pyrazin-3-yl]-1- methylcyclobutanol (<strong>[867160-71-2]OSI-906</strong>) (Compound 1 ):A vessel was charged with DMF (79 kg), c/s-3-(8-amino-1-bromo-imidazo[1 ,5-a]pyrazin- 3-yl)-1 -methylcyclobutanol (16.725 kg), 2-phenyl-7-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)-quinoline (22.4 kg), triphenylphosphine (0.586 kg), cesium carbonate (36.7 kg) and water (20.1 kg). The reaction mixture was degassed and heated to 95-105 C and a solution of palladium acetate (0.125 kg) in DMF (9.8 kg) was added and rinsed in with DMF (5.9 kg). After the reaction was complete, water (154 kg) was added keeping the temperature above 70 C. The resultant slurry was cooled and the solid was collected by filtration. After washing with a mixture of DMF (9.4 kg) and water (23.4 kg) and then water (67 kg) the solid was suspended in water (167 kg) at 50 C and the pH of the mixture was adjusted to 2.9 with 6N hydrochloric acid (10.9 kg). The resultant yellow slurry was filtered to remove the major impurities and the cake was washed with water (67 kg). The acid solution was stirred at 50-55 C and polymer bound trimercaptotriazine resin (MP-TMT) (4.9 kg) was added. The mixture was stirred for 23 hours, the resin was removed by filtration and the cake was washed with water (58 kg).The resultant acid solution was diluted with 2-propanol (82 kg), the temperature was adjusted to 35-45 C and the pH was adjusted to 5.0 by the addition of 1 N sodium hydroxide solution. The mixture was cooled, the yellow product was collected by filtration and was washed with water (33 kg). The solid was re-suspended in water (157 kg) stirred, filtered and washed with water (125 kg). The solid was dried under vacuum at 45-55 C (the resulting material was a hemihydrate of <strong>[867160-71-2]OSI-906</strong> designated Form C) and was then stirred in refluxing 2- propanol (157 kg) for 3 hours. The mixture was cooled and the solid was isolated by filtration. After washing with 2-propanol (26.7 kg), the product was dried at 45-55 C under vacuum to yield 15.6 kg (65% yield) of <strong>[867160-71-2]OSI-906</strong>. The resulting material was an anhydrous crystalline form of <strong>[867160-71-2]OSI-906</strong> designated Form A.
7
[ 867160-71-2 ]
[ 1356958-77-4 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water;
Example 4: c/s-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1 -(2-phenyl-quinolin-7-yl)- imidazo[1 ,5-a]pyrazin-7-ium chlorideThis material was prepared by heating <strong>[867160-71-2]OSI-906</strong> with an equivalent of hydrochloric acid in water and then allowing the solution to cool. The solid was filtered from the cooled mixture and dried. The XRPD and DSC suggest a semi-crystalline material. The DSC, XRPD, and 1H NMR (300MHz, DMSO-d6) of the sample were recorded and are reproduced in Figs. 1 , 2, and 3, respectively.
cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium hydrogensulfate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; In ethanol;
Example 6: c/s-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1 -(2-phenyl-quinolin-7-yl)- imidazo[1 ,5-a]pyrazin-7-ium hydrogen sulfateThis material was prepared by heating <strong>[867160-71-2]OSI-906</strong> with a slight excess of sulfuric acid in ethanol and then allowing the mixture to cool. The solid was collected by filtration and dried. The DSC, XRPD, and 1H NMR (300MHz, DMSO-d6) of the sample were recorded and are reproduced in Figs. 7, 8, and 9, respectively.
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