oxan-4-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:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step B To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (13 mL) were added Cs2CO3 (2.9 g, 8.9 mmol) and methanesulfonic acid tetrahydropyran-4-yl ester (0.64 g, 3.6 mmol) sequentially. The reaction mixture was heated at 120° C. for 3 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (40-60% EtOAc in hexanes) to give 4-(3-methoxy-4-nitrophenoxy)tetrahydro-2H-pyran as a yellow oil (0.4 g, 53%). The mixture was cooled to room temperature The mixture was extracted with ethyl acetate three times The combined organic extract was washed with water, brine dried over MgSO4 concentrated The residue was purified by chromatography (40-60% EtOAc in hexanes)

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

Procedure: Step A To a solution of 4-hydroxytetrahydropyran (4.5 g, 44 mmol) (Aldrich) in dichloromethane (90 mL) at 0° C. was added triethylamine (5.4 g, 53 mmol), and methanesulfonyl chloride (3.73 mL, 48 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 1 h, then at room temperature for 1.5 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid tetrahydropyran-4-yl ester as a white solid (Yield 8 g, 100%). at room temperature for 1.5 h extracted with dichloromethane The organic layer was separated washed with water, brine dried over MgSO4 concentrated

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10 kg tetrahydropyran-4-ol are dissolved in a mixture of 50 L toluene and 10.4 kg triethylamine. 11.55 kg methanesulfonyl chloride in 100 ml toluene are added while maintaining the internal temperature below 20° C. by cooling, and the addition funnel is rinsed with 50 ml toluene. The stirring is continued for one hour. The precipitate is filtered and the filter cake is washed twice with 20 L toluene each. The filtrate is concentrated by vaccum evaporation (60 L were distilled of), seeding crystals and 50 L methylcyclohexane are added. The suspension is cooled to 2° C. After 1 h the product is isolated by filtration, washed with 30 L methylcyclohexane and dried at 30° C. 16.6 kg of the product are obtained as a white solid. Yield: 94%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (2H, m), 1.92-2.00 (2 H, m), 3.19 (3H, s), 3.42-3.49 (2H, m), 3.77-3.83 (2H, m), 4.80-4.88 (1H, m). while maintaining the internal temperature below 20° C. by cooling the addition funnel is rinsed with 50 ml toluene The precipitate is filtered the filter cake is washed twice with 20 L toluene each The filtrate is concentrated by vaccum evaporation (60 L were distilled of) are added After 1 h the product is isolated by filtration washed with 30 L methylcyclohexane dried at 30° C

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

Procedure: Methanesulphonyl chloride (1.82 ml, 23.5 mmol) was added dropwise over 10 minutes to an ice-cold solution of tetrahydro-2H-pyran-4-ol (2.0 g, 19.6 mmol) and triethylamine (3.56 ml, 25.5 mmol) in dichloromethane (20 ml), and the reaction then stirred at room temperature for 72 hours. The reaction was washed with saturated aqueous sodium bicarbonate solution (10 ml), dried (MgSO4) and evaporated under reduced pressure to give an orange oil, that solidified on standing, 3.1 g. the reaction The reaction was washed with saturated aqueous sodium bicarbonate solution (10 ml) dried (MgSO4) evaporated under reduced pressure to give an orange oil

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-3,5-dimethylphenol (3 g) in N-methyl-pyrrolidone (10 mL) is slowly added Cs2CO3 (9.7 g) and tetrahydro-2H-pyran-4-yl methanesulfonate (5.4 g). The mixture is heated for 3 hours at 140° C. After cooling to room temperature the mixture is partitioned between saturated aqueous Na2CO3 solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (MgSO4). The solvents are evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 1.2 g; LC (method 4): tR=1.83 min. After cooling to room temperature the mixture is partitioned between saturated aqueous Na2CO3 solution and ethyl acetate The aqueous phase is extracted with ethyl acetate the combined organic phases are dried (MgSO4) The solvents are evaporated the residue is purified by HPLC on reversed phase

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

Procedure: To a solution of tetrahydro-2H-pyran-4-ol (20 g) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30° C. The mixture is stirred for 12 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf=0.36 (silicagel, petrole ether/ethyl acetate 1:1); Mass spectrum (ESI+): m/z=198 [M+NH4]+. the temperature below 30° C The precipitate is filtered off washed twice with tetrahydrofuran The combined organic phases are concentrated partitioned between ethyl acetate and water The organic phase is dried (Na2SO4) concentrated

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

Procedure: In a manner similar to the method described in Example 4a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-pyran-4-yl ester (Example 32a) and potassium carbonate in dimethylformamide to give a solid. MS (H+), 225. to give a solid

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

Procedure: In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (6 g, 39 mmol) (Aldrich) was reacted with methanesulfonic acid tetrahydropyran-4-yl ester (10 g, 46 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformamide to give 5-chloro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 2 g, 64%).