1,5-dioxa-9-azaspiro[5.5]undecane

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: In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 597 mg (3.80 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane to give 86 mg (61% of theory) of the title compound.

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: In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.622 g (3.96 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane, from Step 4 Example 196, 0.500 g (1.3 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, and 15 mL of dry pyridine. The reaction was stirred at room temperature for 5 hours, then the solvent was removed by evaporation. The residue was dissolved in 50 mL of methylene chloride, which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water, dried over anhydrous sodium sulfate, filtered and dried. The product was purified by recrystallization from ethanol/water, isolated by filtration and dried under vacuum to afford 0.576 g of the title compound, mp 177°-178° C., MS (DCl/NH3) M/Z 504 (M+H) (base). Analysis calculated for C25H24F3N3O5 : C, 59.64; H, 4.80; N, 8.35. Found: C, 61.13; H, 5.09; N, 8.36. In a reaction similar to that of Step 1, Example 387 into oven-dried glassware maintained under dry N2 the solvent was removed by evaporation The residue was dissolved in 50 mL of methylene chloride which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water dried over anhydrous sodium sulfate filtered dried The product was purified by recrystallization from ethanol/water isolated by filtration dried under vacuum

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

Procedure: In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.622 g (3.96 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane, from Step 4 Example 196, 0.500 g (1.3 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, and 15 mL of dry pyridine. The reaction was stirred at room temperature for 5 hours, then the solvent was removed by evaporation. The residue was dissolved in 50 mL of methylene chloride, which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water, dried over anhydrous sodium sulfate, filtered and dried. The product was purified by recrystallization from ethanol/water, isolated by filtration and dried under vacuum to afford 0.576 g of the title compound, mp 177°-178° C., MS (DCl/NH3) M/Z 504 (M+H) (base). Analysis calculated for C25H24F3N3O5 : C, 59.64; H, 4.80; N, 8.35. Found: C, 61.13; H, 5.09; N, 8.36. In a reaction similar to that of Step 1, Example 387 into oven-dried glassware maintained under dry N2 the solvent was removed by evaporation The residue was dissolved in 50 mL of methylene chloride which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water dried over anhydrous sodium sulfate filtered dried The product was purified by recrystallization from ethanol/water isolated by filtration dried under vacuum

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

Procedure: To a solution of 1,5-dioxa-9-aza spiro[5.5]undecane (15.0 g, 95.4 mmol) and triethylamine (17.6 mL, 126 mmol) in THF (140 mL) cooled to 0° C. was added dropwise a solution of benzyl chloroformate (14 mL, 97.5 mmol) dissolved in THF (30 mL). The resulting mixture was stirred at room temp for 18 h. After diluting with EtOAc, the mixture was washed with water and brine and dried (Na2SO4). Concentration gave yellow oil that was purified by flash chromatography eluting with 20%-50% EtOAc/hexane to give the title compound as colorless oil (18.9 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ: 7.36-7.27 (5H, m), 5.09 (2H, s), 3.89-3.85 (4H, m), 3.51-3.47 (4H, m), 1.87-1.66 (6H, m). LCMS (M+H) calcd for C16H22NO4: 292.15; found: 292.00. the mixture was washed with water and brine dried (Na2SO4) Concentration gave yellow oil that was purified by flash chromatography eluting with 20%-50% EtOAc/hexane

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

Procedure: In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 597 mg (3.80 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane to give 86 mg (61% of theory) of the title compound.

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

Procedure: In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 597 mg (3.80 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane to give 86 mg (61% of theory) of the title compound.

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

Procedure: In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-4,6-dihydropyrimidine-5-carbonitrile are reacted with 597 mg (3.80 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane to give 86 mg (61% of theory) of the title compound.

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

Procedure: In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.622 g (3.96 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane, from Step 4 Example 196, 0.500 g (1.3 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, and 15 mL of dry pyridine. The reaction was stirred at room temperature for 5 hours, then the solvent was removed by evaporation. The residue was dissolved in 50 mL of methylene chloride, which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water, dried over anhydrous sodium sulfate, filtered and dried. The product was purified by recrystallization from ethanol/water, isolated by filtration and dried under vacuum to afford 0.576 g of the title compound, mp 177°-178° C., MS (DCl/NH3) M/Z 504 (M+H) (base). Analysis calculated for C25H24F3N3O5 : C, 59.64; H, 4.80; N, 8.35. Found: C, 61.13; H, 5.09; N, 8.36. In a reaction similar to that of Step 1, Example 387 into oven-dried glassware maintained under dry N2 the solvent was removed by evaporation The residue was dissolved in 50 mL of methylene chloride which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water dried over anhydrous sodium sulfate filtered dried The product was purified by recrystallization from ethanol/water isolated by filtration dried under vacuum