6-amino-2,2-dimethyl-4H-1,4-benzoxazin-3-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask was added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (7.82 g, 37.3 mmol), 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (8.60 g, 44.7 mmol, Example #3, Step C), K2CO3 (6.18 g, 44.7 mmol) and t-BuOH (249 mL). To the mixture was added Pd2dba3 (2.05 g, 2.24 mmol) and X-Phos (2.13 g, 4.47 mmol). The flask was de-gassed and vented with N2 three times. The mixture was heated to about 85° C. and stirred overnight. The mixture was diluted with EtOAc (700 mL) and washed with water (700 mL). The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic layers were dried with MgSO4, filtered through a pad of Celite® and concentrated in vacuo. The material was purified by column chromatography (300 g silica gel) using a gradient of 30 to 100% EtOAc/DCM. The material was suspended in 30% EtOAc/DCM (150 mL) and heated to about 77° C. with stirring. MeOH (20 mL) was added gradually to the hot solution until a clear solution resulted. The mixture was allowed to stir for about 1 h and then cooled to rt. The precipitate formed was collected by filtration to give a solid. The mother liquor was kept in the refrigerator overnight and the resulting precipitate was collected by filtration to yield a second batch of the product. The two solids were combined. The material was then suspended in DCM and filtered. The precipitate was dried in a vacuum oven at about 70° C. for about 18 h. The material was then pulverized using a mortar and pestle and dried in the vacuum oven at about 80° C. for about 16 h. The material was taken up in IPA (200 mL) and the suspension was heated to about 50° C. with stirring for about 2 h. The mixture was brought to rt and filtered. The precipitate was dried in a vacuum oven at about 80° C. for about 16 h. The material was dissolved in MeOH (200 mL) and evaporated under reduced pressure. The residue was dried in a vacuum oven at about 80° C. for about 16 h. The material was suspended in water (200 mL) and sonicated for about 10 min then stirred vigorously for about 1 h. The mixture was filtered and the precipitate was dried in a vacuum oven at about 80° C. for about 20 h to provide 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (5.0 g, 37%): LC/MS (Table 2, Method c) Rt=1.87 min.; MS m/z: 366 (M+H)+. Syk IC50=A The flask was de-gassed The mixture was diluted with EtOAc (700 mL) washed with water (700 mL) The aqueous layer was extracted with EtOAc (2×300 mL) The combined organic layers were dried with MgSO4 filtered through a pad of Celite® concentrated in vacuo The material was purified by column chromatography (300 g silica gel) heated to about 77° C. with stirring MeOH (20 mL) was added gradually to the hot solution until a clear solution resulted to stir for about 1 h cooled to rt The precipitate formed was collected by filtration to give a solid was kept in the refrigerator overnight the resulting precipitate was collected by filtration to yield a second batch of the product filtered The precipitate was dried in a vacuum oven at about 70° C. for about 18 h dried in the vacuum oven at about 80° C. for about 16 h the suspension was heated to about 50° C. with stirring for about 2 h was brought to rt filtered The precipitate was dried in a vacuum oven at about 80° C. for about 16 h The material was dissolved in MeOH (200 mL) evaporated under reduced pressure The residue was dried in a vacuum oven at about 80° C. for about 16 h sonicated for about 10 min then stirred vigorously for about 1 h The mixture was filtered the precipitate was dried in a vacuum oven at about 80° C. for about 20 h

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl (4-(2-(tert-butyldimethylsilyloxy)ethyl)-1-(2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.40 g, 0.587 mmol, prepared using AH from 2-iodoethanol with TBDMSCl, AF with 1-benzylpiperidine-4-carbonitrile [Ryan] with tert-butyl(2-iodoethoxy)dimethylsilane, AE, O with Boc2O, G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [Arkpharm]) and an aqueous solution of aqueous HCl (4 M, 7.34 mL, 29.4 mmol) were dissolved in 1,4-dioxane (15 mL) and stirred for about 4 h at rt. The mixture was concentrated under vacuum and the residue was purified by Prep-TLC (EtOAc/pet ether 1:2) to give 6-(4-(4-(aminomethyl)-4-(2-hydroxyethyl)piperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one (0.121 g, 43%): LC/MS (Table 2, Method h) Rt=1.69 min.; MS m/z: 467 (M+H)+. Syk IC50=A The mixture was concentrated under vacuum the residue was purified by Prep-TLC (EtOAc/pet ether 1:2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl (4-(2-(tert-butyldimethylsilyloxy)ethyl)-1-(2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.40 g, 0.587 mmol, prepared using AH from 2-iodoethanol with TBDMSCl, AF with 1-benzylpiperidine-4-carbonitrile [Ryan] with tert-butyl(2-iodoethoxy)dimethylsilane, AE, O with Boc2O, G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [Arkpharm]) and an aqueous solution of aqueous HCl (4 M, 7.34 mL, 29.4 mmol) were dissolved in 1,4-dioxane (15 mL) and stirred for about 4 h at rt. The mixture was concentrated under vacuum and the residue was purified by Prep-TLC (EtOAc/pet ether 1:2) to give 6-(4-(4-(aminomethyl)-4-(2-hydroxyethyl)piperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one (0.121 g, 43%): LC/MS (Table 2, Method h) Rt=1.69 min.; MS m/z: 467 (M+H)+. Syk IC50=A The mixture was concentrated under vacuum the residue was purified by Prep-TLC (EtOAc/pet ether 1:2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-(4-(4-amino-3-(tert-butyldimethylsilyloxy)azepan-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.400 g, 0.724 mmol, prepared using F from Preparation #AH.1, O with Boc2O, K, A with 2,4-dichlorofuro[3,2-d]pyrimidine [Arkpharm], B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ArkPharm] and C) and TBAF (0.378 g, 1.45 mmol) in THF (10 mL) was stirred at about 25° C. for about 4 h. The mixture was concentrated and purified by preparatory HPLC (Table 2, Method t) to give 6-(4-(4-amino-3-hydroxyazepan-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.11 g, 35%): LC/MS (Table 2, Method h) Rt=1.69 min.; MS m/z: 439 (M+H)+. Syk IC50=B prepared The mixture was concentrated purified by preparatory HPLC (Table 2, Method t)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-(4-(4-(azidomethyl)-4-methoxypiperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.030 g, 0.063 mmol, prepared using C from tert-butyl 4-(azidomethyl)-4-methoxypiperidine-1-carboxylate [WO 2010/080864, Example 257], A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ArkPharm]) and triphenylphosphine (0.025 g, 0.094 mmol) in THF (16 mL) and water (2 mL) was stirred at about 100° C. overnight. The organic phase was removed and diluted with water. The aqueous phase was neutralized with aqueous 2 N NaOH and extracted with EtOAc. The combined organic phase was washed with brine and dried over Na2SO4, filtered, concentrated under vacuum and purified by HPLC (Table 2, Method v) to afford 6-(4-(4-(aminomethyl)-4-methoxypiperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.022 g, 76%). LC/MS (Table 2, method h) Rt=1.77 min.; MS m/z: 453 (M+H)+. Syk IC50=A prepared The organic phase was removed diluted with water extracted with EtOAc The combined organic phase was washed with brine dried over Na2SO4 filtered concentrated under vacuum purified by HPLC (Table 2, Method v)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-(4-(4-(azidomethyl)-4-methoxypiperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.030 g, 0.063 mmol, prepared using C from tert-butyl 4-(azidomethyl)-4-methoxypiperidine-1-carboxylate [WO 2010/080864, Example 257], A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ArkPharm]) and triphenylphosphine (0.025 g, 0.094 mmol) in THF (16 mL) and water (2 mL) was stirred at about 100° C. overnight. The organic phase was removed and diluted with water. The aqueous phase was neutralized with aqueous 2 N NaOH and extracted with EtOAc. The combined organic phase was washed with brine and dried over Na2SO4, filtered, concentrated under vacuum and purified by HPLC (Table 2, Method v) to afford 6-(4-(4-(aminomethyl)-4-methoxypiperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.022 g, 76%). LC/MS (Table 2, method h) Rt=1.77 min.; MS m/z: 453 (M+H)+. Syk IC50=A prepared The organic phase was removed diluted with water extracted with EtOAc The combined organic phase was washed with brine dried over Na2SO4 filtered concentrated under vacuum purified by HPLC (Table 2, Method v)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.056 g, 0.30 mmol) in dimethylsulfoxide (1 mL) was added DIPEA (0.12 mL, 0.60 mmol) and 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.085 g, 0.44 mmol). After heating at 100° C. for 15 h, the mixture was diluted with ethylacetate and sequentially washed with saturated NaHCO3 and brine. The organic extracts were dried over Na2SO4 and concentrated to give 6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.05 g). sequentially washed with saturated NaHCO3 and brine The organic extracts were dried over Na2SO4 concentrated

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.056 g, 0.30 mmol) in dimethylsulfoxide (1 mL) was added DIPEA (0.12 mL, 0.60 mmol) and 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.085 g, 0.44 mmol). After heating at 100° C. for 15 h, the mixture was diluted with ethylacetate and sequentially washed with saturated NaHCO3 and brine. The organic extracts were dried over Na2SO4 and concentrated to give 6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.05 g). sequentially washed with saturated NaHCO3 and brine The organic extracts were dried over Na2SO4 concentrated

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask was added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (7.82 g, 37.3 mmol), 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (8.60 g, 44.7 mmol, Example #3, Step C), K2CO3 (6.18 g, 44.7 mmol) and t-BuOH (249 mL). To the mixture was added Pd2dba3 (2.05 g, 2.24 mmol) and X-Phos (2.13 g, 4.47 mmol). The flask was de-gassed and vented with N2 three times. The mixture was heated to about 85° C. and stirred overnight. The mixture was diluted with EtOAc (700 mL) and washed with water (700 mL). The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic layers were dried with MgSO4, filtered through a pad of Celite® and concentrated in vacuo. The material was purified by column chromatography (300 g silica gel) using a gradient of 30 to 100% EtOAc/DCM. The material was suspended in 30% EtOAc/DCM (150 mL) and heated to about 77° C. with stirring. MeOH (20 mL) was added gradually to the hot solution until a clear solution resulted. The mixture was allowed to stir for about 1 h and then cooled to rt. The precipitate formed was collected by filtration to give a solid. The mother liquor was kept in the refrigerator overnight and the resulting precipitate was collected by filtration to yield a second batch of the product. The two solids were combined. The material was then suspended in DCM and filtered. The precipitate was dried in a vacuum oven at about 70° C. for about 18 h. The material was then pulverized using a mortar and pestle and dried in the vacuum oven at about 80° C. for about 16 h. The material was taken up in IPA (200 mL) and the suspension was heated to about 50° C. with stirring for about 2 h. The mixture was brought to rt and filtered. The precipitate was dried in a vacuum oven at about 80° C. for about 16 h. The material was dissolved in MeOH (200 mL) and evaporated under reduced pressure. The residue was dried in a vacuum oven at about 80° C. for about 16 h. The material was suspended in water (200 mL) and sonicated for about 10 min then stirred vigorously for about 1 h. The mixture was filtered and the precipitate was dried in a vacuum oven at about 80° C. for about 20 h to provide 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (5.0 g, 37%): LC/MS (Table 2, Method c) Rt=1.87 min.; MS m/z: 366 (M+H)+. Syk IC50=A The flask was de-gassed The mixture was diluted with EtOAc (700 mL) washed with water (700 mL) The aqueous layer was extracted with EtOAc (2×300 mL) The combined organic layers were dried with MgSO4 filtered through a pad of Celite® concentrated in vacuo The material was purified by column chromatography (300 g silica gel) heated to about 77° C. with stirring MeOH (20 mL) was added gradually to the hot solution until a clear solution resulted to stir for about 1 h cooled to rt The precipitate formed was collected by filtration to give a solid was kept in the refrigerator overnight the resulting precipitate was collected by filtration to yield a second batch of the product filtered The precipitate was dried in a vacuum oven at about 70° C. for about 18 h dried in the vacuum oven at about 80° C. for about 16 h the suspension was heated to about 50° C. with stirring for about 2 h was brought to rt filtered The precipitate was dried in a vacuum oven at about 80° C. for about 16 h The material was dissolved in MeOH (200 mL) evaporated under reduced pressure The residue was dried in a vacuum oven at about 80° C. for about 16 h sonicated for about 10 min then stirred vigorously for about 1 h The mixture was filtered the precipitate was dried in a vacuum oven at about 80° C. for about 20 h