4-methyloxan-4-ol

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

Procedure: A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel, a thermometer and a nitrogen introducing pipe, was charged with 4.64 g (40.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 20.0 g of methylene chloride and further charged with 0.24 g (2.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 6.78 g (60.0 mmoles) of 2-chloroacetyl chloride. Subsequently, 6.37 g (63.0 mmoles) of triethylamine was added dropwise at room temperature over 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 hours. To this reaction mixed solution, 1.11 g (24.0 mmoles) of ethanol was added dropwise, and subsequently, 20.0 g of water was added dropwise; and the mixture was stirred for 20 minutes. This reaction mixed solution was separated into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 20 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of water and concentrated in vacuo, thereby obtaining 6.09 g (31.6 mmoles) of 4-chloroacetoxy-4-methyltetrahydropyran (yield: 79%). A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel After completion of the dropwise addition was added dropwise and the mixture was stirred for 20 minutes This reaction mixed solution was separated into an aqueous layer The aqueous layer was extracted twice with 20 mL of methylene chloride the mixture was washed once with 10 mL of water concentrated in vacuo

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

Procedure: A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel, a thermometer and a nitrogen introducing pipe, was charged with 4.64 g (40.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 20.0 g of methylene chloride and further charged with 0.24 g (2.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 6.78 g (60.0 mmoles) of 2-chloroacetyl chloride. Subsequently, 6.37 g (63.0 mmoles) of triethylamine was added dropwise at room temperature over 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 hours. To this reaction mixed solution, 1.11 g (24.0 mmoles) of ethanol was added dropwise, and subsequently, 20.0 g of water was added dropwise; and the mixture was stirred for 20 minutes. This reaction mixed solution was separated into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 20 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of water and concentrated in vacuo, thereby obtaining 6.09 g (31.6 mmoles) of 4-chloroacetoxy-4-methyltetrahydropyran (yield: 79%). A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel After completion of the dropwise addition was added dropwise and the mixture was stirred for 20 minutes This reaction mixed solution was separated into an aqueous layer The aqueous layer was extracted twice with 20 mL of methylene chloride the mixture was washed once with 10 mL of water concentrated in vacuo

Conditions: temp:3.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A three-necked flask having an inner volume of 100 mL, which was equipped with a thermometer, was charged with 3.48 g (30.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 30.0 g of methylene chloride, and the inside of the flask was purged with nitrogen. This mixed solution was cooled with ice water; 4.40 mL (45.0 mmoles) of methacryloly chloride was subsequently added; and 6.27 mL (45.0 mmoles) of triethylamine was further added dropwise slowly while maintaining the temperature of the reaction solution at 2 to 5° C. After completion of the dropwise addition, stirring was continued at 4 to 5° C. for 3 hours. 20 mL of water and 20 mL of a saturated sodium hydrogencarbonate aqueous solution were successively added slowly to the obtained reaction mixed solution, and after stirring for a while, the mixture was allowed to stand, thereby separating it into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 30 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of saturated salt water, dried over anhydrous magnesium sulfate and then concentrated in vacuo; and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1 (volume ratio)), thereby obtaining 3.03 g (16.45 mmoles) of 4-methacryloyloxy-4-methyltetrahydropyran having the following physical properties as a colorless transparent liquid (purity: 99%, yield: 55%). A three-necked flask having an inner volume of 100 mL, which was equipped with a thermometer the inside of the flask was purged with nitrogen This mixed solution was cooled with ice water 4.40 mL (45.0 mmoles) of methacryloly chloride was subsequently added After completion of the dropwise addition mixed solution after stirring for a while separating it into an aqueous layer The aqueous layer was extracted twice with 30 mL of methylene chloride the mixture was washed once with 10 mL of saturated salt water dried over anhydrous magnesium sulfate concentrated in vacuo and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1 (volume ratio))

Conditions: temp:3.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A three-necked flask having an inner volume of 100 mL, which was equipped with a thermometer, was charged with 3.48 g (30.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 30.0 g of methylene chloride, and the inside of the flask was purged with nitrogen. This mixed solution was cooled with ice water; 4.40 mL (45.0 mmoles) of methacryloly chloride was subsequently added; and 6.27 mL (45.0 mmoles) of triethylamine was further added dropwise slowly while maintaining the temperature of the reaction solution at 2 to 5° C. After completion of the dropwise addition, stirring was continued at 4 to 5° C. for 3 hours. 20 mL of water and 20 mL of a saturated sodium hydrogencarbonate aqueous solution were successively added slowly to the obtained reaction mixed solution, and after stirring for a while, the mixture was allowed to stand, thereby separating it into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 30 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of saturated salt water, dried over anhydrous magnesium sulfate and then concentrated in vacuo; and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1 (volume ratio)), thereby obtaining 3.03 g (16.45 mmoles) of 4-methacryloyloxy-4-methyltetrahydropyran having the following physical properties as a colorless transparent liquid (purity: 99%, yield: 55%). A three-necked flask having an inner volume of 100 mL, which was equipped with a thermometer the inside of the flask was purged with nitrogen This mixed solution was cooled with ice water 4.40 mL (45.0 mmoles) of methacryloly chloride was subsequently added After completion of the dropwise addition mixed solution after stirring for a while separating it into an aqueous layer The aqueous layer was extracted twice with 30 mL of methylene chloride the mixture was washed once with 10 mL of saturated salt water dried over anhydrous magnesium sulfate concentrated in vacuo and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1 (volume ratio))

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

Procedure: To a solution of 4-methyltetrahydro-2H-pyran-4-ol obtained in Example 7-1 in chloroacetonitrile (0.65 mL), was added a mixture of acetic acid and conc. sulfuric acid (1/1, 1.6 mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hrs. with cooling on an ice bath

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

Procedure: To a solution of 4-methyltetrahydro-2H-pyran-4-ol obtained in Example 7-1 in chloroacetonitrile (0.65 mL), was added a mixture of acetic acid and conc. sulfuric acid (1/1, 1.6 mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hrs. with cooling on an ice bath

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

Procedure: A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel, a thermometer and a nitrogen introducing pipe, was charged with 4.64 g (40.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 20.0 g of methylene chloride and further charged with 0.24 g (2.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 6.78 g (60.0 mmoles) of 2-chloroacetyl chloride. Subsequently, 6.37 g (63.0 mmoles) of triethylamine was added dropwise at room temperature over 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 hours. To this reaction mixed solution, 1.11 g (24.0 mmoles) of ethanol was added dropwise, and subsequently, 20.0 g of water was added dropwise; and the mixture was stirred for 20 minutes. This reaction mixed solution was separated into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 20 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of water and concentrated in vacuo, thereby obtaining 6.09 g (31.6 mmoles) of 4-chloroacetoxy-4-methyltetrahydropyran (yield: 79%). A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel After completion of the dropwise addition was added dropwise and the mixture was stirred for 20 minutes This reaction mixed solution was separated into an aqueous layer The aqueous layer was extracted twice with 20 mL of methylene chloride the mixture was washed once with 10 mL of water concentrated in vacuo

Conditions: temp:3.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A three-necked flask having an inner volume of 100 mL, which was equipped with a thermometer, was charged with 3.48 g (30.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 30.0 g of methylene chloride, and the inside of the flask was purged with nitrogen. This mixed solution was cooled with ice water; 4.40 mL (45.0 mmoles) of methacryloly chloride was subsequently added; and 6.27 mL (45.0 mmoles) of triethylamine was further added dropwise slowly while maintaining the temperature of the reaction solution at 2 to 5° C. After completion of the dropwise addition, stirring was continued at 4 to 5° C. for 3 hours. 20 mL of water and 20 mL of a saturated sodium hydrogencarbonate aqueous solution were successively added slowly to the obtained reaction mixed solution, and after stirring for a while, the mixture was allowed to stand, thereby separating it into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 30 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of saturated salt water, dried over anhydrous magnesium sulfate and then concentrated in vacuo; and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1 (volume ratio)), thereby obtaining 3.03 g (16.45 mmoles) of 4-methacryloyloxy-4-methyltetrahydropyran having the following physical properties as a colorless transparent liquid (purity: 99%, yield: 55%). A three-necked flask having an inner volume of 100 mL, which was equipped with a thermometer the inside of the flask was purged with nitrogen This mixed solution was cooled with ice water 4.40 mL (45.0 mmoles) of methacryloly chloride was subsequently added After completion of the dropwise addition mixed solution after stirring for a while separating it into an aqueous layer The aqueous layer was extracted twice with 30 mL of methylene chloride the mixture was washed once with 10 mL of saturated salt water dried over anhydrous magnesium sulfate concentrated in vacuo and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1 (volume ratio))

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

Procedure: To a suspension of sodium hydride, 60% in mineral oil (207 mg, 5.17 mmol) in THF (20 mL) was added 4-methyltetrahydro-2H-pyran-4-ol (500 mg, 4.30 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (931 mg, 4.30 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. At room temperature, to the reaction mixture was added sat. aq. NH4Cl (1 mL) upon which brief and significant effervescence was observed. The mixture was transferred to a 250 mL separatory funnel and was diluted with Et2O (50 mL). The solution was washed with water:brine (25 mL: 25 mL). The aq. phase was extracted with EtOAc (100 mL). The combined organics were dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was dissolved in acetone and then concentrated onto Celite in vacuo. The resulting powder was subjected to SiO2 purification on the Biotage system [90 g SiO2 column, hexanes:EtOAc 90:10 to 60:40 over 8 CV] to get the product as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.48-8.39 (m, 1H), 7.87-7.76 (m, 1H), 7.30-7.24 (m, 2H), 7.16-7.09 (m, 1H), 3.83-3.69 (m, 4H), 2.29-2.16 (m, 2H), 1.80 (ddd, J=14.3, 8.9, 5.9 Hz, 2H), 1.66 (s, 3H). The formed slurry was stirred at 0° C. for 30 min stirred for 2 h The mixture was transferred to a 250 mL separatory funnel The solution was washed with water The aq. phase was extracted with EtOAc (100 mL) The combined organics were dried over MgSO4 filtered then concentrated in vacuo The resulting residue was dissolved in acetone concentrated onto Celite in vacuo The resulting powder was subjected to SiO2 purification on the Biotage system [90 g SiO2 column, hexanes:EtOAc 90:10 to 60:40 over 8 CV]

Conditions: temp:5.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a three-necked flask having an inner volume of 50 mL equipped with a thermometer and a stirring apparatus were charged 1.00 g (8.51 mmol) of 4-methyltetrahydropyran-4-ol, 1.0 mg of 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl, 4.0 g of isopropyl ether, and 1.42 g (8.94 mmol) of 2-methacryloyloxyethyl isocyanate. After the mixture was cooled by ice water to an inner temperature of 5° C., 250 mg (2.55 mmol) of methanesulfonic acid was added dropwise. After stirring the reaction mixture for 10 hours with the reaction temperature maintained at 5 to 6° C., 4.0 g of a saturated aqueous NaHCO3 solution was added dropwise with the inner temperature maintained at 10° C. or less and, after completion of the dropwise addition, the mixture was allowed to stand still for 30 minutes. The organic layer (upper layer) formed was separated and the aqueous layer (lower layer) was extracted twice with 4.0 g of isopropyl ether. All the separated organic layers were combined, washed with 4.0 g of distilled water, and the organic layer was concentrated under reduced pressure to obtain 2.29 g of a concentrate. The concentrate was dissolved in 10 g of hexane at 30° C. and the solution was cooled to −10° C. at a rate of 10° C./hour. The crystals which precipitated were separated by filtration and the crystals obtained were dried under vacuum (26.7 Pa) at 30° C. for 2 hours to obtain 1.10 g (purity 97.0%, 3.93 mmol, yield: 46.2%) of 4-methyltetrahydropyran-4-yl (2-methacryloyloxyethyl)carbamate. In a three-necked flask having an inner volume of 50 mL equipped with a thermometer was added dropwise maintained at 10° C. or less after completion of the dropwise addition to stand still for 30 minutes The organic layer (upper layer) formed was separated the aqueous layer (lower layer) was extracted twice with 4.0 g of isopropyl ether washed with 4.0 g of distilled water the organic layer was concentrated under reduced pressure to obtain 2.29 g of a concentrate the solution was cooled to −10° C. at a rate of 10° C./hour The crystals which precipitated were separated by filtration the crystals obtained were dried under vacuum (26.7 Pa) at 30° C. for 2 hours

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

Procedure: To a solution of 4-methyltetrahydro-2H-pyran-4-ol obtained in Example 7-1 in chloroacetonitrile (0.65 mL), was added a mixture of acetic acid and conc. sulfuric acid (1/1, 1.6 mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hrs. with cooling on an ice bath

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

Procedure: A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel, a thermometer and a nitrogen introducing pipe, was charged with 4.64 g (40.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 20.0 g of methylene chloride and further charged with 0.24 g (2.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 6.78 g (60.0 mmoles) of 2-chloroacetyl chloride. Subsequently, 6.37 g (63.0 mmoles) of triethylamine was added dropwise at room temperature over 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 hours. To this reaction mixed solution, 1.11 g (24.0 mmoles) of ethanol was added dropwise, and subsequently, 20.0 g of water was added dropwise; and the mixture was stirred for 20 minutes. This reaction mixed solution was separated into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 20 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of water and concentrated in vacuo, thereby obtaining 6.09 g (31.6 mmoles) of 4-chloroacetoxy-4-methyltetrahydropyran (yield: 79%). A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel After completion of the dropwise addition was added dropwise and the mixture was stirred for 20 minutes This reaction mixed solution was separated into an aqueous layer The aqueous layer was extracted twice with 20 mL of methylene chloride the mixture was washed once with 10 mL of water concentrated in vacuo