tert-butyl N-[2-amino-2-(3-chlorophenyl)ethyl]carbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 4 supra) (686 mg, 2.5 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude [4-(3-{2-[2-tert-butoxycarbonylamino-1-(3-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester. (Yield 140 mg, 32.5%). The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2-(3-Chloro-phenyl)-2-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 4 supra) by following the method in Example 61.

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of [2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 6.2 mmol) in THF (10 mL) and methanol (10 mL) was added hydrazine hydrate (3.1 g, 62 mmol). The mixture was heated at 55° C. for 1 hour. Then it was concentrated to dryness, dissolved in H2O (5 mL) and extracted with ethyl acetate (50 mL). The organic mixture was concentrated and purified by column chromatography (methanol:dichloromethane, 1:100) to afford [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester. (Yield 1.325 g, 79%). LC-MS: [M+H]+ 271. Then it was concentrated to dryness dissolved in H2O (5 mL) extracted with ethyl acetate (50 mL) The organic mixture was concentrated purified by column chromatography (methanol:dichloromethane, 1:100)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of [3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 41 supra) (0.403 g, 1.0 mmol), [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 78 supra) (0.406 g, 1.5 mmol), Pd2(dba)3(60 mg), Davephos (80 mg), K2CO3 (207 mg, 1.5 mmol) in dioxane (25 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 130° C. overnight. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography (CH2Cl2:MeOH, 50:1 to 20:1) to give crude (2-(3-chloro-phenyl)-2-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester. (Yield 210 mg). LC-MS: [M+H]+ 593. was bubbled with N2 for several minutes The solution was then cooled to room temperature filtered The filtrate was concentrated under reduced pressure The obtained residue was purified by chromatography (CH2Cl2:MeOH, 50:1 to 20:1)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (210 mg, 0.563 mmol) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 78 supra) (611 mg, 2.25 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to 4:1) to afford crude (2-(3-chloro-phenyl)-2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester. (Yield 150 mg). LC-MS: [M+H]+ 564. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to 4:1)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of [2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethy]-carbamic acid tert-butyl ester (2.5 g, 6.2 mmol) in THF (10 mL) and methanol (10 mL) was added hydrazine hydrate (3.1 g, 62 mmol). The mixture was heated a 55° C. for 1 hour. Then it was concentrated to dryness, dissolved in H2O (5 mL) and extracted with ethyl acetate (50 mL). The organic mixture was concentrated and purified by column chromatography (methanol:dichloromethane, 1:100) to afford [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester. (Yield 1.325 g, 79%). LC-MS: [M+H]+ 271. Then it was concentrated to dryness dissolved in H2O (5 mL) extracted with ethyl acetate (50 mL) The organic mixture was concentrated purified by column chromatography (methanol:dichloromethane, 1:100)