tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

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:; See reaction.notes.procedure_details.

Procedure: HATU (0.924 g) was added in one portion to a stirred solution at 0° C. of 4-isopropylthiazole-2-carboxylic acid (0.32 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step b) (0.547 g) and triethylamine (0.781 mL) in DMF (12 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.54 g. The mixture was partitioned between ethyl acetate and brine the organic layer was washed twice with brine dried over sodium sulphate filtered the solvent evaporated under reduced pressure The crude product was purified by flash silica chromatography Pure fractions were evaporated to dryness

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

Procedure: HATU (0.924 g) was added in one portion to a stirred solution at 0° C. of 4-isopropylthiazole-2-carboxylic acid (0.32 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step b) (0.547 g) and triethylamine (0.781 mL) in DMF (12 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.54 g. The mixture was partitioned between ethyl acetate and brine the organic layer was washed twice with brine dried over sodium sulphate filtered the solvent evaporated under reduced pressure The crude product was purified by flash silica chromatography Pure fractions were evaporated to dryness

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

Procedure: A solution of tert-butyl 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step a) (8.2 g) in THF (100 mL) was treated dropwise with borane THF complex (1M in THF, 91 mL) and the resultant mixture heated at 55° C. for 2 hours. Borane dimethylsulfide complex (2M in THF, 15.17 mL) was added and the resultant mixture heated at 55° C. for 2 hours. The mixture was cooled to room temperature and quenched with methanol, then the solvents were evaporated under reduced pressure. The residue was dissolved in methanol (250 mL) and the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) and the resultant mixture was heated at reflux for 6 hours. Further N1,N2-dimethylethane-1,2-diamine (3 g) was added and heated at reflux continued for 6 hours. The mixture was cooled to room temperature and the solvents evaporated under reduced pressure, the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 7.40 g. quenched with methanol the solvents were evaporated under reduced pressure The residue was dissolved in methanol (250 mL) the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) the resultant mixture was heated at reflux for 6 hours Further N1,N2-dimethylethane-1,2-diamine (3 g) was added heated at reflux The mixture was cooled to room temperature the solvents evaporated under reduced pressure the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane Pure fractions were evaporated to dryness

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

Procedure: A solution of tert-butyl 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step a) (8.2 g) in THF (100 mL) was treated dropwise with borane THF complex (1M in THF, 91 mL) and the resultant mixture heated at 55° C. for 2 hours. Borane dimethylsulfide complex (2M in THF, 15.17 mL) was added and the resultant mixture heated at 55° C. for 2 hours. The mixture was cooled to room temperature and quenched with methanol, then the solvents were evaporated under reduced pressure. The residue was dissolved in methanol (250 mL) and the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) and the resultant mixture was heated at reflux for 6 hours. Further N1,N2-dimethylethane-1,2-diamine (3 g) was added and heated at reflux continued for 6 hours. The mixture was cooled to room temperature and the solvents evaporated under reduced pressure, the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 7.40 g. quenched with methanol the solvents were evaporated under reduced pressure The residue was dissolved in methanol (250 mL) the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) the resultant mixture was heated at reflux for 6 hours Further N1,N2-dimethylethane-1,2-diamine (3 g) was added heated at reflux The mixture was cooled to room temperature the solvents evaporated under reduced pressure the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane Pure fractions were evaporated to dryness

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

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

Procedure: To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (100 mg, 0.352 mmol) in dichloroethane (10 mL) were added 1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester (110 mg, 0.376 mmol) and sodium triacetoxyborohydride (113 mg, 0.533 mmol) and the resulting solution stirred at RT for 3 h. The reaction was quenched with water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by column chromatography to give the title compound as a white solid (98 mg, 53%) [M+H]+ 524.3 The reaction was quenched with water washed with MeOH then eluted with 2 M NH3 in MeOH The resulting residue was then purified by column chromatography

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

Procedure: To a mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (5.80 g) and dioxane (100 mL), 1 M aqueous sodium hydroxide (24.9 mL) and benzyl chloroformate (3.55 mL) were added sequentially under ice cooling and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1-1:1) to give 4-benzyl 9-tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate (8.06 g) as a colorless syrup. were added sequentially under ice cooling The reaction mixture was concentrated under reduced pressure extracted with ethyl acetate The organic layer was concentrated under reduced pressure the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1-1:1)

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

Procedure: HATU (0.924 g) was added in one portion to a stirred solution at 0° C. of 4-isopropylthiazole-2-carboxylic acid (0.32 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step b) (0.547 g) and triethylamine (0.781 mL) in DMF (12 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.54 g. The mixture was partitioned between ethyl acetate and brine the organic layer was washed twice with brine dried over sodium sulphate filtered the solvent evaporated under reduced pressure The crude product was purified by flash silica chromatography Pure fractions were evaporated to dryness

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

Procedure: A solution of tert-butyl 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step a) (8.2 g) in THF (100 mL) was treated dropwise with borane THF complex (1M in THF, 91 mL) and the resultant mixture heated at 55° C. for 2 hours. Borane dimethylsulfide complex (2M in THF, 15.17 mL) was added and the resultant mixture heated at 55° C. for 2 hours. The mixture was cooled to room temperature and quenched with methanol, then the solvents were evaporated under reduced pressure. The residue was dissolved in methanol (250 mL) and the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) and the resultant mixture was heated at reflux for 6 hours. Further N1,N2-dimethylethane-1,2-diamine (3 g) was added and heated at reflux continued for 6 hours. The mixture was cooled to room temperature and the solvents evaporated under reduced pressure, the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 7.40 g. quenched with methanol the solvents were evaporated under reduced pressure The residue was dissolved in methanol (250 mL) the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) the resultant mixture was heated at reflux for 6 hours Further N1,N2-dimethylethane-1,2-diamine (3 g) was added heated at reflux The mixture was cooled to room temperature the solvents evaporated under reduced pressure the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane Pure fractions were evaporated to dryness