1-oxa-3,8-diazaspiro[4.5]decan-2-one

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 was prepared according to Example 106 Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (19.5 mg, 0.05 mmol) and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one (7.6 mg, 0.05 mmol) as the starting materials.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vial was added 8-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (0.100 g, 0.238 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] with 1-oxa-3,8-diazaspiro[4.5]decan-2-one [Chembridge], B with Example #3, Step B and C) in MeOH (3 mL). Then aqueous NaOH (5 M, 0.715 mL, 3.58 mmol) was added. The mixture was heated in a microwave at about 100° C. for about 30 min (300 psi maximum pressure, 2 min ramp, 250 max watts). Aqueous NaOH (5 M, 0.350 mL, 1.75 mmol) was added. The mixture was heated in a microwave at about 120° C. for about 40 min (300 psi maximum pressure, 2 min ramp, 250 max watts). The mixture was filtered and the filtrate was cooled on ice and the precipitate formed was collected via filtration and dried in a vacuum oven at about 75° C. for about 15 h to give 4-(aminomethyl)-1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-yl)piperidin-4-ol (0.07 g, 75%): LC/MS (Table 2, Method c) Rt=1.44 min.; MS m/z: 394 (M+H)+. Syk IC50=A prepared The mixture was heated in a microwave at about 120° C. for about 40 min (300 psi maximum pressure, 2 min ramp, 250 max watts) The mixture was filtered the filtrate was cooled on ice the precipitate formed was collected via filtration dried in a vacuum oven at about 75° C. for about 15 h

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vial was added 8-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (0.100 g, 0.238 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] with 1-oxa-3,8-diazaspiro[4.5]decan-2-one [Chembridge], B with Example #3, Step B and C) in MeOH (3 mL). Then aqueous NaOH (5 M, 0.715 mL, 3.58 mmol) was added. The mixture was heated in a microwave at about 100° C. for about 30 min (300 psi maximum pressure, 2 min ramp, 250 max watts). Aqueous NaOH (5 M, 0.350 mL, 1.75 mmol) was added. The mixture was heated in a microwave at about 120° C. for about 40 min (300 psi maximum pressure, 2 min ramp, 250 max watts). The mixture was filtered and the filtrate was cooled on ice and the precipitate formed was collected via filtration and dried in a vacuum oven at about 75° C. for about 15 h to give 4-(aminomethyl)-1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-yl)piperidin-4-ol (0.07 g, 75%): LC/MS (Table 2, Method c) Rt=1.44 min.; MS m/z: 394 (M+H)+. Syk IC50=A prepared The mixture was heated in a microwave at about 120° C. for about 40 min (300 psi maximum pressure, 2 min ramp, 250 max watts) The mixture was filtered the filtrate was cooled on ice the precipitate formed was collected via filtration dried in a vacuum oven at about 75° C. for about 15 h

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

Procedure: A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (150 mg), triethylamine (150 μL), 1-oxa-3,8-diazaspiro[4.5]decan-2-one (110 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (82 mg, yield 43%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 224° C. the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried (MgSO4) concentrated

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

Procedure: The title compound was prepared according to Example 106 Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (19.5 mg, 0.05 mmol) and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one (7.6 mg, 0.05 mmol) as the starting materials.

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

Procedure: The title compound was prepared according to Example 106 Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (19.5 mg, 0.05 mmol) and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one (7.6 mg, 0.05 mmol) as the starting materials.

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

Procedure: A mixture of 3.94 g of 3-(2-bromoethyl)indole, 2.74 g of 1-oxa-3,8-diazaspiro[4.5]decan-2-one, 2 g of triethylamine and 10 ml N,N-dimethylformamide is stirred at 50° for 16 hours. The mixture is cooled to room temperature and 150 ml of water is added with stirring The aqueous layer is decanted from the residue which adheres to the walls of the flask. The residue is washed with 100 ml water following by 100 ml diethyl ether. The residue is dissolved in a minimum amount of 10% (v/v) methanol-dichloromethane and the resulting solution is filtered through 25 g silica gel with 150 ml of 10% (v/v) methanol-dichloromethane. Evaporation of the filtrate followed by crystallization with diethyl ether affords 2.35 g of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 183°-186° (d). with stirring The aqueous layer is decanted from the residue which The residue is washed with 100 ml water following by 100 ml diethyl ether The residue is dissolved in a minimum amount of 10% (v/v) methanol-dichloromethane the resulting solution is filtered through 25 g silica gel with 150 ml of 10% (v/v) methanol-dichloromethane Evaporation of the filtrate followed by crystallization with diethyl ether

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

Procedure: To a mixture of 9.5 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one and 75 ml water, at 0°, is added 6.3 g sodium bicarbonate and 10.9 g benzyl chloroformate. The mixture is stirred 18 hours at 0°, acidified with 10 N hydrochloric acid and stirred four hours at room temperature. The mixture is extracted with three 50 ml portions of dichloromethane. Removal of solvent affords 14.4 g 8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 126°-128°. stirred four hours at room temperature The mixture is extracted with three 50 ml portions of dichloromethane Removal of solvent

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

Procedure: A mixture of 6.2 g 8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 50 ml ethanol and 0.5 g, 10% palladium on carbon is hydrogenated at 60 psi and 50° for 18 hours. After filtration and removal of solvent there is obtained 4.2 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 158°-161°. After filtration and removal of solvent

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

Procedure: Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.