methyl 4-methyloxane-4-carboxylate

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: Methyl tetrahydropyran-4-carboxylate (2.88 g, 20.0 mmol) was dissolved in THF (100 mL), and a 2.0 mol/L solution of lithium diisopropylamide in THF (22.0 ml, 44.0 mmol) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. Methyl iodide (4.98 ml, 40.0 mmol) was added dropwise to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford methyl 4-methyltetrahydropyran-4-carboxylate (1.93 g, 61%). at 0° C. by stirring for 1 hour followed by extraction with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate the solvent was distilled away under reduced pressure the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1)

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

Procedure: A solution of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (5.00 g, 31.6 mmol) in 1:1:1 dioxane/water/MeOH (60 mL) was treated with lithium hydroxide hydrate (5.31 g, 126 mmol) and stirred at RT overnight. The mixture was partially concentrated, diluted with water and EtOAc and acidified to pH=1 with 6M HCl. The layers were separated, the aqueous layer extracted with additional EtOAc (50 mL) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 4-methyltetrahydro-2H-pyran-4-carboxylic acid (4.61 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 3.65 (dt, J=11.8, 4.3 Hz, 2H), 3.33-3.32 (m, 2H), 1.87-1.86 (m, 2H), 1.35 (ddd, J=13.5, 9.9, 4.1 Hz, 2H), 1.13 (s, 3H). The mixture was partially concentrated diluted with water and EtOAc The layers were separated the aqueous layer extracted with additional EtOAc (50 mL) the combined organics were washed with brine dried over Na2SO4 concentrated to dryness

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

Procedure: A 78° C. solution of 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester (Regan, J. et al. J. Med. Chem. 2002, 45, 2994-3008; 9.9 g, 63 mmol) in CH2Cl2 (400 mL) was treated with DIBAL-H (1.0 M in CH2Cl2; 125 mL, 125 mmol). The resulting mixture was stirred for 1 h, and then was diluted with EtOAc (200 mL) and satd. aq. NH4Cl. The mixture was treated with satd. aq. sodium potassium tartrate, allowed to warm to rt, and stirred for 45 min. The mixture was extracted with CH2Cl2 (4×), and the combined extracts were washed with satd. aq. NaCl, dried, and concentrated. Chromatography (EtOAc/hexanes) afforded the title compound as a colorless oil (5.6 g 69%). The spectral data matched that reported in PCT Intl. Pat. Appl. Publ. No. WO 2006/001752. The mixture was treated with satd stirred for 45 min The mixture was extracted with CH2Cl2 (4×) the combined extracts were washed with satd aq. NaCl, dried concentrated

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

Procedure: A 78° C. solution of 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester (Regan, J. et al. J. Med. Chem. 2002, 45, 2994-3008; 9.9 g, 63 mmol) in CH2Cl2 (400 mL) was treated with DIBAL-H (1.0 M in CH2Cl2; 125 mL, 125 mmol). The resulting mixture was stirred for 1 h, and then was diluted with EtOAc (200 mL) and satd. aq. NH4Cl. The mixture was treated with satd. aq. sodium potassium tartrate, allowed to warm to rt, and stirred for 45 min. The mixture was extracted with CH2Cl2 (4×), and the combined extracts were washed with satd. aq. NaCl, dried, and concentrated. Chromatography (EtOAc/hexanes) afforded the title compound as a colorless oil (5.6 g 69%). The spectral data matched that reported in PCT Intl. Pat. Appl. Publ. No. WO 2006/001752. The mixture was treated with satd stirred for 45 min The mixture was extracted with CH2Cl2 (4×) the combined extracts were washed with satd aq. NaCl, dried concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction is removed from the bath and stirred for 10 min. It is then cooled to −78° C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6 mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is added and the reaction allowed to reach rt. The reaction is then quenched with 1 N HCl (200 mL) and extracted with EtOAc. The organic layer is dried and evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester. MS (ESI) m/z 159.3 (M+1). The reaction is removed from the bath After 30 min to reach rt The reaction is then quenched with 1 N HCl (200 mL) extracted with EtOAc The organic layer is dried evaporated

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

Procedure: A solution of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (5.00 g, 31.6 mmol) in 1:1:1 dioxane/water/MeOH (60 mL) was treated with lithium hydroxide hydrate (5.31 g, 126 mmol) and stirred at RT overnight. The mixture was partially concentrated, diluted with water and EtOAc and acidified to pH=1 with 6M HCl. The layers were separated, the aqueous layer extracted with additional EtOAc (50 mL) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 4-methyltetrahydro-2H-pyran-4-carboxylic acid (4.61 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 3.65 (dt, J=11.8, 4.3 Hz, 2H), 3.33-3.32 (m, 2H), 1.87-1.86 (m, 2H), 1.35 (ddd, J=13.5, 9.9, 4.1 Hz, 2H), 1.13 (s, 3H). The mixture was partially concentrated diluted with water and EtOAc The layers were separated the aqueous layer extracted with additional EtOAc (50 mL) the combined organics were washed with brine dried over Na2SO4 concentrated to dryness

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

Procedure: To a solution of acetonitrile (300 μL, 5.7 mmol) in THF (20 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 10.1 mL, 17.2 mmol) followed by the dropwise addition of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (1.36 g, 8.62 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜10 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (911 mg, 5.74 mmol) was added. The reaction was acidified to pH 1 by the addition of conc hydrochloric acid and the resulting heterogeneous mixture was heated to 70° C. for 5 hr, was then cooled to RT and concentrated in vacuo to a volume of ˜20 mL. The mixture was diluted with water (30 mL) and adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-50%, gradient elution) to afford the title compound, Intermediate 21, as a yellow solid (550 mg, 32%); Rt 1.48 min (Method 2); m/z 272 (M+H)+, (ES+). The resulting mixture was concentrated in vacuo to a volume of ˜10 mL was added the resulting heterogeneous mixture was heated to 70° C. for 5 hr was then cooled to RT concentrated in vacuo to a volume of ˜20 mL The mixture was diluted with water (30 mL) adjusted to pH 12 by the addition of 2M aq NaOH was then extracted with ethyl acetate (2×20 mL) The combined extracts were washed with brine (30 mL) dried evaporated in vacuo The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-50%, gradient elution)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction is removed from the bath and stirred for 10 min. It is then cooled to −78° C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6 mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is added and the reaction allowed to reach rt. The reaction is then quenched with 1N HCl (200 mL) and extracted with EtOAc. The organic layer is dried and evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester. MS (ESI) m/z 159.3 (M+1). The reaction is removed from the bath After 30 min to reach rt The reaction is then quenched with 1N HCl (200 mL) extracted with EtOAc The organic layer is dried evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction is removed from the bath and stirred for 10 min. It is then cooled to −78° C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6 mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is added and the reaction allowed to reach rt. The reaction is then quenched with 1 N HCl (200 mL) and extracted with EtOAc. The organic layer is dried and evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester. MS (ESI) m/z 159.3 (M+1). The reaction is removed from the bath After 30 min to reach rt The reaction is then quenched with 1 N HCl (200 mL) extracted with EtOAc The organic layer is dried evaporated