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

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

Procedure: A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.694 g) in DMF (13 mL) was treated with triethylamine (1.3 mL), followed by 2-isopropylthiazole-5-carboxylic acid (example 55, step b) (0.406 g) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g). The resulting mixture was stirred at RT for 16 h. DMF was removed in vacuo. The residue was taken up in EtOAc (40 mL) and washed with saturated sodium bicarbonate solution (2×40 mL), water (40 mL) and brine (40 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The viscous orange oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a viscous orange oil. Yield 0.765 g. DMF was removed in vacuo washed with saturated sodium bicarbonate solution (2×40 mL), water (40 mL) and brine (40 mL) dried over sodium sulphate filtered evaporated in vacuo The viscous orange oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM

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

Procedure: A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.694 g) in DMF (13 mL) was treated with triethylamine (1.3 mL), followed by 2-isopropylthiazole-5-carboxylic acid (example 55, step b) (0.406 g) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g). The resulting mixture was stirred at RT for 16 h. DMF was removed in vacuo. The residue was taken up in EtOAc (40 mL) and washed with saturated sodium bicarbonate solution (2×40 mL), water (40 mL) and brine (40 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The viscous orange oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a viscous orange oil. Yield 0.765 g. DMF was removed in vacuo washed with saturated sodium bicarbonate solution (2×40 mL), water (40 mL) and brine (40 mL) dried over sodium sulphate filtered evaporated in vacuo The viscous orange oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM

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

Procedure: A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.60 g) in DMF (11 mL) was treated with triethylamine (1.1 mL), followed by 2-phenyl-1,3-thiazole-4-carboxylic acid (0.421 g) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.09 g). The resulting mixture was stirred at RT for 7 h. DMF was removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with saturated sodium bicarbonate solution (2×30 mL), water (30 mL) and brine (30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The brown oil was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a brown solid. Yield 0.857 g. DMF was removed in vacuo washed with saturated sodium bicarbonate solution (2×30 mL), water (30 mL) and brine (30 mL) dried over sodium sulphate filtered evaporated in vacuo The brown oil was purified by silica gel chromatography eluting with 0-10% MeOH in DCM

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

Procedure: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.45 g) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.8 g), 1,3-benzothiazol-2-carboxylic acid (0.588 g) and triethylamine (1.51 mL) in DMF (15 mL) and the resulting mixture stirred for 16 h. The volume of DMF was reduced in vacuo and the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a yellow oil. Yield 0.83 g. the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL) The organic layer was washed with water (30 mL) and brine (30 mL) dried over magnesium sulphate filtered evaporated in vacuo Purification eluting with 0-10% methanol in dichloromethane

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

Procedure: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.45 g) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.8 g), 1,3-benzothiazol-2-carboxylic acid (0.588 g) and triethylamine (1.51 mL) in DMF (15 mL) and the resulting mixture stirred for 16 h. The volume of DMF was reduced in vacuo and the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a yellow oil. Yield 0.83 g. the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL) The organic layer was washed with water (30 mL) and brine (30 mL) dried over magnesium sulphate filtered evaporated in vacuo Purification eluting with 0-10% methanol in dichloromethane

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

Procedure: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.91 g) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.5 g), 5-methyl-thiophene-3-carboxylic acid (0.243 g) and triethylamine (0.95 mL) in DMF (10 mL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into brine (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were washed with water (150 mL), brine (150 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a clear oil. Yield 0.34 g. extracted with ethyl acetate (3×50 mL) The combined organic solutions were washed with water (150 mL), brine (150 mL) dried over sodium sulphate filtered evaporated in vacuo Purification eluting with 0-10% methanol in dichloromethane

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: HATU (1.15 g) was added in one portion to a solution at 0° C. of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.682 g) and 5-ethylthiophene-3-carboxylic acid (0.364 g) and triethylamine (1.3 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction 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 50% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the ‘BOC’ protected intermediate. DCM (10 mL) was added followed by trifluoroacetic acid (10 mL) and the resultant solution allowed to stand at 20° C. for 25 minutes. Toluene (30 mL) was added and the solvents evaporated under reduced pressure. The residue was azeotroped twice with acetonitrile to yield the subtitled compound. Yield 0.950 g. The reaction 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 to afford the ‘BOC’ to stand at 20° C. for 25 minutes the solvents evaporated under reduced pressure The residue was azeotroped twice with acetonitrile

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: HATU (1.15 g) was added in one portion to a solution at 0° C. of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.682 g) and 5-ethylthiophene-3-carboxylic acid (0.364 g) and triethylamine (1.3 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction 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 50% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the ‘BOC’ protected intermediate. DCM (10 mL) was added followed by trifluoroacetic acid (10 mL) and the resultant solution allowed to stand at 20° C. for 25 minutes. Toluene (30 mL) was added and the solvents evaporated under reduced pressure. The residue was azeotroped twice with acetonitrile to yield the subtitled compound. Yield 0.950 g. The reaction 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 to afford the ‘BOC’ to stand at 20° C. for 25 minutes the solvents evaporated under reduced pressure The residue was azeotroped twice with acetonitrile

Conditions: temp:12.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (limiting reagent) and 2-isopropylthiazole-4-carboxylic acid (1.1 molar equivalents) was suspended in 2-MeTHF (10 volumes) and cooled to 10-15° C. Triethylamine (7.2 molar equivalents) was added in portions at 10-15° C. The thick suspension was cooled to 5-10° C. and T3P (1.3 molar equivalents of a 1.57M solution in THF) was added dropwise at 5-10° C. over 0.5 hr. The reaction mixture was allowed to warm to ambient temperature (35 min) and stirred for 2.5 hr. The mixture was diluted with water (10 volumes, 5° C. exotherm) and the mixture vigorously stirred; the aqueous (pH 10) was separated and extracted with 2-MeTHF (2×2 volumes). The combined organics were washed with saturated aq sodium bicarbonate soln (2 volumes) and water (2×2 volumes). The organic phase was evaporated and azeotroped with MeCN (2×2 volumes) to give a brown gum, which was dried at 35° C. in vacuo for 24 hr. Yield: 89% of theoretical. The thick suspension was cooled to 5-10° C. to warm to ambient temperature (35 min) the mixture vigorously stirred the aqueous (pH 10) was separated extracted with 2-MeTHF (2×2 volumes) The combined organics were washed with saturated aq sodium bicarbonate soln (2 volumes) and water (2×2 volumes) The organic phase was evaporated azeotroped with MeCN (2×2 volumes) to give a brown gum, which was dried at 35° C. in vacuo for 24 hr

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.6 g) and thiophene-2,5-dicarboxylic acid (1.7 g) in DMF (10 mL) was treated with triethylamine (2.75 mL) and cooled to 0° C. HATU (1.013 g) was added and the mixture stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and brine containing acetic acid (2 mL), the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 1% acetic acid in ethyl acetate as solvent. This material was dissolved in THF (30 mL), treated with carbonyldiimidazole (0.332 g) and the mixture was allowed to stand at 45° C. for 1 hour. Methanol (20 mL) was added and the reaction heated at 50° C. for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 40% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.45 g. The mixture was partitioned between ethyl acetate and brine containing acetic acid (2 mL) the organic layer was washed twice with brine dried over sodium sulphate filtered the solvent evaporated under reduced pressure The residue was purified by flash silica chromatography This material was dissolved in THF (30 mL) treated with carbonyldiimidazole (0.332 g) to stand at 45° C. for 1 hour Methanol (20 mL) was added the reaction heated at 50° C. for 30 minutes The solvent was removed under reduced pressure the residue was partitioned between ethyl acetate and brine The organic layer was 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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.6 g) and thiophene-2,5-dicarboxylic acid (1.7 g) in DMF (10 mL) was treated with triethylamine (2.75 mL) and cooled to 0° C. HATU (1.013 g) was added and the mixture stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and brine containing acetic acid (2 mL), the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 1% acetic acid in ethyl acetate as solvent. This material was dissolved in THF (30 mL), treated with carbonyldiimidazole (0.332 g) and the mixture was allowed to stand at 45° C. for 1 hour. Methanol (20 mL) was added and the reaction heated at 50° C. for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 40% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.45 g. The mixture was partitioned between ethyl acetate and brine containing acetic acid (2 mL) the organic layer was washed twice with brine dried over sodium sulphate filtered the solvent evaporated under reduced pressure The residue was purified by flash silica chromatography This material was dissolved in THF (30 mL) treated with carbonyldiimidazole (0.332 g) to stand at 45° C. for 1 hour Methanol (20 mL) was added the reaction heated at 50° C. for 30 minutes The solvent was removed under reduced pressure the residue was partitioned between ethyl acetate and brine The organic layer was 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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.594 g) and 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.4 g) in DMF (10 mL) was treated with triethylamine (0.848 mL) and cooled to 0° C. HATU (1.003 g) was added and the mixture stirred at 20° C. 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 eluting with 40% ethyl acetate in isohexane to yield the product as the free base. This was dissolved in dichloromethane (40 mL) and treated with trifluoroacetic acid (10 mL) and then the mixture was allowed to stand at 20° C. for 1 hour. Toluene (60 mL) was added and the solvent removed under reduced pressure to afford the subtitled compound. Yield 0.740 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 eluting with 40% ethyl acetate in isohexane to yield the product as the free base to stand at 20° C. for 1 hour the solvent removed under reduced pressure