1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate

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:

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: A suspension of sodium hydride (72.6 mg, 1.82 mmol) in DMF (1 mL); was cooled in an ice/water bath and treated with a solution of 4-iodopyrazole (242 mg, 1.21 mmol) in DMF (2 mL) added dropwise under an atmosphere of nitrogen in 5 min. After stirring in the cold for another 30 min, a solution of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (321 mg, 1.33 mmol) in DMF (2 mL) was added dropwise at 0° C. The mixture was warmed to RT and was then immersed in 150° C. oil bath and stirred for 2 h. The mixture was treated with water (15 mL), extracted with EtOAc (3×20 mL). The extracts were washed with water (3×15 mL), brine (15 mL), dried over MgSO4. After concentration in vacuo, a brown solid was obtained. It was dissolved in MeOH and after water was added, a solid formed, which was filtered off to give 266 mg (66%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 7.49 (s, 1 H), 4.23 (tt, J=4.2, 11.2 Hz, 1 H), 2.34-2.20 (m, 1 H), 2.21-1.96 (m, 4 H), 1.95-1.81 (m, 2 H), 1.82-1.66 (m, 3 H), 1.33-1.22 (m, 2 H); MS (ESI): 334.96 [M+H]+; HPLC tR=3.26 min. was cooled in an ice/water bath added dropwise under an atmosphere of nitrogen in 5 min was then immersed in 150° C. stirred for 2 h extracted with EtOAc (3×20 mL) The extracts were washed with water (3×15 mL), brine (15 mL) dried over MgSO4 After concentration in vacuo a brown solid was obtained a solid formed which was filtered off

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.10 g, 6.81 mmol), triethylamine (1.21 mL, 8.67 mmol) in DCM (25.2 mL) was cooled in an ice/water bath and treated with methanesulfonyl chloride (675 μL, 8.67 mmol) added dropwise under an atmosphere of nitrogen. The mixture was stirred at 25° C. overnight. The mixture was treated with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2×50 mL). The extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo leaving a beige oil which was recrystallized from hexanes (22 mL) to give 1.59 g (98%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.61-1.68 (m, 2H), 1.82-1.90 (m, 2H), 1.94-2.08 (m, 4H), 3.02 (s, 3H), 3.91-4.00 (m, 4H), 4.82-4.88 (m, 1H); MS (ESI): 237.10 [M+H]+; HPLC tR=2.54 min. added dropwise under an atmosphere of nitrogen extracted with DCM (2×50 mL) The extracts were washed with brine (50 mL) dried over MgSO4 concentrated in vacuo leaving a beige oil which was recrystallized from hexanes (22 mL)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 16.0 g potassium carbonate and 20.0 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added at 50° C. to 20.0 g 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150 ml N,N-dimethylformamide and the mixture is vigorously stirred for 18 hours at 80° C. To complete the reaction potassium carbonate and 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are each added three times and in each case the mixture is stirred for several hours at 80° C. The reaction mixture is cooled and slowly combined with a total of 500 ml of water. The precipitate is suction filtered, washed with water and dried. each added three times in each case the mixture is stirred for several hours at 80° C The reaction mixture is cooled filtered washed with water dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 12.5 g potassium carbonate and 16 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan (cf. for example Journal of Medicinal Chemistry (1992), 35(12), 2243-7) in 125 ml dimethylformamide are added at 50° C. to 18.1 g 4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline (cf. for example Bioorganic & Medicinal Chemistry Letters (2006), 16(18), 4908-4912) and the mixture is stirred for 18 hours at 80° C. Another 4.7 g potassium carbonate and 4.0 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added and the mixture is stirred for a further 7 hours at 80° C. The reaction mixture is cooled, diluted with water and ethyl acetate and the precipitate formed is suction filtered and dried. the mixture is stirred for a further 7 hours at 80° C The reaction mixture is cooled the precipitate formed filtered dried

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