ethyl 4-(hydroxymethyl)oxane-4-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Intermediate 3 Ethyl 4-(Methanesulfonyloxy)methyltetrahydropyran-4-carboxylate Methanesulfonyl chloride (4.6 ml) was added to a solution of intermediate 2 (1 1.0 g) at 0° C. in dichloromethane (30 ml), followed by triethylamine (8.0 ml). The mixture was stirred for 1 h, then washed with citric acid (5% aq, 30 ml), saturated sodium bicarbonate and brine. The organic layer was separated, and then dried (MgSO4) and evaporated to give the title compound as colourless oil (15.2 g). washed with citric acid (5% aq, 30 ml), saturated sodium bicarbonate and brine The organic layer was separated dried (MgSO4) evaporated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Intermediate 3 Ethyl 4-(Methanesulfonyloxy)methyltetrahydropyran-4-carboxylate Methanesulfonyl chloride (4.6 ml) was added to a solution of intermediate 2 (1 1.0 g) at 0° C. in dichloromethane (30 ml), followed by triethylamine (8.0 ml). The mixture was stirred for 1 h, then washed with citric acid (5% aq, 30 ml), saturated sodium bicarbonate and brine. The organic layer was separated, and then dried (MgSO4) and evaporated to give the title compound as colourless oil (15.2 g). washed with citric acid (5% aq, 30 ml), saturated sodium bicarbonate and brine The organic layer was separated dried (MgSO4) evaporated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of lithium hydroxide monohydrate (4.46 Kg) in methanol (44 liters) and water (11 Kg) was added ethyl 4-hydroxymethyl-tetrahydropyran-4-carboxylate (8.0 Kg) The mixture was refluxed for 30 minutes, then solvent removed under reduced pressure. The mixture was cooled to 20° C., methyl tert-butyl ether (14.8 Kg) added, stirred for 10 minutes, and allowed to settle. The top organic layer was separated. This was repeated twice more, then the remaining mixture cooled to -10° C., and a solution of 31% hydrochloric acid (13 Kg) in water (3 Kg) added, maintaining the temperature below 5° C. The mixture was extracted several times with tetrahydrofuran, and the combined organic phases dried over magnesium sulfate. Approximately 90% of the tetrahydrofuran was removed, and the remaining solution added to a mixture of hexane (64.5 Kg) and methyl tert-butylether (23.7 Kg) with stirring. The precipitated solid material was filtered off and dried under reduced pressure at 60° C., to give 4-hydroxymethyl-tetrahydropyran-4-carboxylic acid (3.7 Kg), the compound of Formula (9a). was refluxed for 30 minutes solvent removed under reduced pressure methyl tert-butyl ether (14.8 Kg) added The top organic layer was separated the remaining mixture cooled to -10° C. a solution of 31% hydrochloric acid (13 Kg) in water (3 Kg) added maintaining the temperature below 5° C The mixture was extracted several times with tetrahydrofuran the combined organic phases dried over magnesium sulfate Approximately 90% of the tetrahydrofuran was removed the remaining solution added to a mixture of hexane (64.5 Kg) and methyl tert-butylether (23.7 Kg) with stirring The precipitated solid material was filtered off dried under reduced pressure at 60° C.

反応条件: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diethyl tetrahydro-4H-pyran-4,4-dicarboxylate, the compound of Formula (7a), (12 Kg) in toluene (104 Kg) was cooled to between -30° C. to -35° C., and diisobutylaluminum hydride (69 Kg) was added at such a rate so as to maintain a reaction temperature of -25° C. After the addition was complete, the temperature was raised to 15° C. over 3 hours, and the reaction stirred until all starting material was consumed. The mixture was then recooled to -15° C. and allowed to stand overnight. The product was partitioned between ethyl acetate (54 Kg), ethanol (48 Kg), and saturated sodium sulfate solution (60 liters), and the mixture stirred overnight at 250C. The precipitated salts were filtered off, washed with tetrahydrofuran, and the filtrate washed with brine and separated. The organic layer was dried over magnesium sulfate and solvent removed under reduced pressure, to give ethyl 4-hydroxymethyltetrahydropyran-4-carboxylate (3.8 Kg), the compound of Formula (8a). was added at such a rate so as After the addition the temperature was raised to 15° C. over 3 hours was consumed was then recooled to -15° C. The product was partitioned between ethyl acetate (54 Kg), ethanol (48 Kg), and saturated sodium sulfate solution (60 liters) the mixture stirred overnight at 250C The precipitated salts were filtered off washed with tetrahydrofuran the filtrate washed with brine separated The organic layer was dried over magnesium sulfate and solvent removed under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium hydroxide monohydrate (16.7 g, 398.5 mmol) was added to a solution of 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid ethyl ester (25.0 g, 132.8 mmol) in 4.5:1 methanol/water (220 mL). The mixture was heated to reflux for 40 minutes and the methanol removed in vacuo by concentration using a bath temperature no higher than 45° C. The aqueous layer was then extracted into diethyl ether (4×100 mL) and the combined ether layers washed twice with 2M sodium hydroxide (15 mL). The combined aqueous base layers were cooled to 0° C., acidified to pH 3.0 with 8M aqueous hydrochloric acid, saturated with solid sodium chloride and extracted with ethyl acetate (8×250 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo. The white fluffy powder residue was recrystallized from the minimum amount of methylene chloride/hexanes to afford pure 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid (17.05 g, 80%). The mixture was heated to reflux for 40 minutes the methanol removed in vacuo by concentration no higher than 45° C The aqueous layer was then extracted into diethyl ether (4×100 mL) the combined ether layers washed twice with 2M sodium hydroxide (15 mL) extracted with ethyl acetate (8×250 mL) The combined organic layers were dried over magnesium sulfate concentrated in vacuo The white fluffy powder residue was recrystallized from the minimum amount of methylene chloride/hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium diisopropylamide was prepared by the addition of 2.5M N-butyl lithium (30.3 mL, 75.6 mmol) in hexanes to a solution of diisopropylamine (10.6 mL, 75.6 mmmol) in tetrahydrofuran (244 mL) at 0° C. and stirring for 20 minutes. Then a solution of tetrahydropyran-4-carboxylic acid ethyl ester (10 g, 63.2 mmol) in tetrahydrofuran (50 mL) was added to the solution of lithium diisopropylamide over 15 minutes at -78° C. The resulting solution was stirred an additional 50 minutes, and solid paraformaldehyde (10 g) was added in one portion. The mixture was slowly allowed to warm to room temperature over 9 hours, diluted with 2M aqueous hydrochloric acid (100 mL), and filtered over a pad of celite pad which was washed with diethyl ether (2×200 mL). The aqueous layer of the filtrate was washed with additional portions of diethyl ether (2×200 mL). The combined organic layers were washed once with 2M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford a slightly impure product 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid ethyl ester (11.5 g, 97%), which was taken into the next reaction without further purification. IR (neat) 3433 (br), 1726 cm-1 ; 1HNMR (CDCl3) δ 1.30 (t, J=7.1 Hz, 3H), 1.57 (ddd, J=13.8, 10.1, 4.4 Hz, 2H), 2.07 (dm, J=13.8 Hz, 2H), 2.30-2.45 (br s, 1H), 3.56 (ddd, J=11.9, 10.3, 2.7 Hz, 2H), 3.66 (s, 2H), 3.82 (dt, J=11.9, 4.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H); 13CNMR (CDCl3) δ 14.25 (q), 30.54 (t), 46.63 (s), 61.04 (t), 64.79 (t), 69.02 (t), 175.24 (s); HRMS Calcd for C9H16O4 : 188.1049. Found: 188.1053. The resulting solution was stirred an additional 50 minutes filtered over a pad of celite pad which was washed with diethyl ether (2×200 mL) The aqueous layer of the filtrate was washed with additional portions of diethyl ether (2×200 mL) The combined organic layers were washed once with 2M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL) dried over magnesium sulfate concentrated in vacuo

反応条件: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1.5M diisobutylaluminum hydride (DIBAL-H) (419 mL, 629 mmol) in toluene was added to a 3-L Morton flask equipped with a nitrogen gas inlet, mechanical stirrer, low temperature thermometer, 500 mL pressure equalizing funnel, and containing tetrahydropyran-4,4-dicarboxylic acid diethyl ester (70.78 g, 307.4 mmol) in toluene (600 mL) at -40° C., at a rate to maintain an internal temperature no higher than -25° C. The mixture was stirred an additional 10 minutes and anhydrous ethanol (595 mL) was added dropwise over 20 minutes maintaining an internal temperature no higher than -15° C. Solid sodium borohydride (11.6 g, 307.4 mmol) was added in three portions over a 15 minute period, the cooling bath was removed, the mixture allowed to warm to room temperature over 1 hour, and saturated aqueous sodium sulfate (325 mL) added over 15 minutes. The mixture was cooled to -15° C., ethyl acetate (250 mL) was added, and the flocculent white precipitate filtered over a pad of celite. The celite pad was washed with ethyl acetate (7×450 mL), the filtrate washed with brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in the minimum amount of ethyl acetate, filtered through a sintered glass funnel containing silica gel (40 g), eluting with ethyl acetate, and the filtrate concentrated in vacuo to afford the hydroxyester, 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid ethyl ester, as a pale yellow oil (48.5 g, 84%). equipped with a nitrogen gas inlet, mechanical stirrer maintaining an internal temperature no higher than -15° C the cooling bath was removed to warm to room temperature over 1 hour saturated aqueous sodium sulfate (325 mL) added over 15 minutes The mixture was cooled to -15° C. ethyl acetate (250 mL) was added the flocculent white precipitate filtered over a pad of celite The celite pad was washed with ethyl acetate (7×450 mL) the filtrate washed with brine (200 mL) dried over magnesium sulfate concentrated in vacuo The residue was dissolved in the minimum amount of ethyl acetate filtered through a sintered glass funnel containing silica gel (40 g) eluting with ethyl acetate the filtrate concentrated in vacuo