4-AMINO-2,2-DIMETHYLTETRAHYDROPYRAN

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

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

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

Procedure: The title compound, MS: m/e=308.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and rac-2,2-dimethyl-tetrahydro-pyran-4-ylamine.

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

Procedure: To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.677 mmol) in THF (3 ml) were added DMF (0.03ml) and oxalylchloride (0.071 ml, 0.813 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 2,2-dimethyltetrahydro-2H-pyran-4-ylamine (175 mg, 1.35 mmol), triethylamine (0.313 ml, 2.25 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective product as a solid material. the solvent was distilled off under reduced pressure The residue was added under ice- the mixture was stirred under ice- cooling for 2 hours extracted with ethyl acetate The extract was washed with water dried over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1)

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

Procedure: To a solution of (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (1.00 g, 2.35 mmol) in THF (10 ml) were added DMF (0.10 ml) and oxalylchloride (0.246 ml, 2.82 mmol), which was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 2,2-dimethyltetrahydro-2H-pyran-4-ylamine (455 mg, 3.53 mmol), triethylamine (1.09 ml, 7.81 mmol) and THF (10 ml), the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to yield the objective product as a solid material. the solvent was distilled off under reduced pressure The residue was added under ice- the mixture was stirred under ice- cooling for 2 hours and at room temperature for 12 hours extracted with ethyl acetate The extract was washed with water dried over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure The residue was recrystallized from ethyl acetate and hexane

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

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

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

Procedure: The reaction of methyl 2,4-dibromobutanoate 17 with 2,2-dimethyltetrahydro-2H-pyran-4-amine 18H yielded methyl 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate as a light brown solid (33%). MS ISP (m/e): 228.3 (100) [(M+H)]+.

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

Procedure: A 0° C. suspension of 2,2-dimethyltetrahydro-2H-pyran-4-amine (0.806 g, 6.24 mmol) in THF (30 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.585 mL, 6.86 mmol), allowed to warm to RT as the cooling bath expired and stirred overnight. The mixture was treated with additional 2-chloroethyl isocyanate (160 μL) and stirred at RT for an additional 24 hours, then concentrated to dryness, the residue dissolved in EtOAc and washed with saturated NH4Cl (1×), NaHCO3 (1×) and brine (1×), dried over MgSO4 and concentrated to dryness to afford 1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (700 mg, 48%) as a yellow oil. MS (ESI) m/z: 235.1 (M+H+). stirred at RT for an additional 24 hours concentrated to dryness the residue dissolved in EtOAc washed with saturated NH4Cl (1×), NaHCO3 (1×) and brine (1×) dried over MgSO4 concentrated to dryness

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

Procedure: The title compound, MS: m/e=308.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and rac-2,2-dimethyl-tetrahydro-pyran-4-ylamine.

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

Procedure: The title compound, MS: m/e=308.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and rac-2,2-dimethyl-tetrahydro-pyran-4-ylamine.

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

Procedure: To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.677 mmol) in THF (3 ml) were added DMF (0.03ml) and oxalylchloride (0.071 ml, 0.813 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 2,2-dimethyltetrahydro-2H-pyran-4-ylamine (175 mg, 1.35 mmol), triethylamine (0.313 ml, 2.25 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective product as a solid material. the solvent was distilled off under reduced pressure The residue was added under ice- the mixture was stirred under ice- cooling for 2 hours extracted with ethyl acetate The extract was washed with water dried over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1)