diethyl 2,2-bis(hydroxymethyl)propanedioate

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: To diethyl-bis-(hydroxymethyl)malonate (50 g) in acetone (50 ml) and benzene (200 ml) is added phosphoric acid (10 g). . The mixture is refluxed while stirring and separating water which distills. When water evolution is complete, the reaction mixture is cooled and the organic layer is separated, stirred with solid sodium carbonate (10 g), filtered and evaporated to give the title product (52 g) (87%) nD26 1.4412. The mixture is refluxed separating water which distills the reaction mixture is cooled the organic layer is separated stirred with solid sodium carbonate (10 g) filtered evaporated

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

実験手順: To diethyl-bis-(hydroxymethyl)malonate (50 g) in acetone (50 ml) and benzene (200 ml) is added phosphoric acid (10 g). . The mixture is refluxed while stirring and separating water which distills. When water evolution is complete, the reaction mixture is cooled and the organic layer is separated, stirred with solid sodium carbonate (10 g), filtered and evaporated to give the title product (52 g) (87%) nD26 1.4412. The mixture is refluxed separating water which distills the reaction mixture is cooled the organic layer is separated stirred with solid sodium carbonate (10 g) filtered evaporated

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

実験手順: Synthesis analogous to Example 13. The bis-(1,1-dimethyl-ethylthiomethyl)-acetic acid was synthesized from diethyl bis-(hydroxymethyl)-malonate by reaction with hydrogen bromide and subsequent replacement of the resulting β,β'-dibromoisobutyric acid with potassium tert.-butylsulfide. Synthesis analogous to Example 13

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

実験手順: Synthesis analogous to Example 13. The bis-(1,1-dimethyl-ethylthiomethyl)-acetic acid was synthesized from diethyl bis-(hydroxymethyl)-malonate by reaction with hydrogen bromide and subsequent replacement of the resulting β,β'-dibromoisobutyric acid with potassium tert.-butylsulfide. Synthesis analogous to Example 13

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

実験手順: To a clear solution of diethyl bis(hydroxymethyl)malonate in 478 mL (6.52 mol) of acetone and 478 mL (8.45 mol) of acetone dimethylacetal was added 1.1 mL (42 mmol) of concentrated sulfuric acid and the reaction was stirred at room temperature overnight (19 hours). After 120 mL of saturated sodium carbonate was added, the mixture was stirred at room temperature for 15 minutes. The layers were separated and the semi-crystalline residue was washed with acetone (2×250 mL). The organics were evaporated. The residue was dispersed in 500 mL of ether and 250 mL of saturated Na2CO3, and stirred for 20 minutes. After the layers were separated, the organic layer was stirred with 250 mL of brine for 5 minutes and the layers separated. The organic layer was dried, evaporated, and placed under vacuum for 3 hours to produce a colorless oil, 527.5 g, in 94% yield. the mixture was stirred at room temperature for 15 minutes The layers were separated the semi-crystalline residue was washed with acetone (2×250 mL) The organics were evaporated The residue was dispersed in 500 mL of ether 250 mL of saturated Na2CO3, and stirred for 20 minutes After the layers were separated the organic layer was stirred with 250 mL of brine for 5 minutes the layers separated The organic layer was dried evaporated placed under vacuum for 3 hours to produce a colorless oil, 527.5 g

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

実験手順: Diethyl 2,2-bis(hydroxymethyl)malonate (20 g, 90.82 mmol), acetone (20 ml), 2,2-dimethoxypropane (20 ml), and concentrated sulfuric acid (0.2 ml) were stirred at 25° C. for 2 days. The reaction was slowly poured into saturated aqueous sodium carbonate. The organic supernatant was separated and concentrated in vacuo. The residue was then dissolved in ether, rinsed with saturated aqueous sodium carbonate and brine, and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford crude 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (21.4 g, 91%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.27 (t, J=7.1 Hz, 6H, 2×CH3), 1.42 (s, 6H, 2×CH3), 4.24 (q, J=7.1 Hz, 4H, 2×OCH2), 4.29 (s, 4H, 2×OCH2). The organic supernatant was separated concentrated in vacuo The residue was then dissolved in ether rinsed with saturated aqueous sodium carbonate and brine dried over magnesium sulfate filtered concentrated in vacuo

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

実験手順: Diethyl 2,2-bis(hydroxymethyl)malonate (20 g, 90.82 mmol), acetone (20 ml), 2,2-dimethoxypropane (20 ml), and concentrated sulfuric acid (0.2 ml) were stirred at 25° C. for 2 days. The reaction was slowly poured into saturated aqueous sodium carbonate. The organic supernatant was separated and concentrated in vacuo. The residue was then dissolved in ether, rinsed with saturated aqueous sodium carbonate and brine, and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford crude 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (21.4 g, 91%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.27 (t, J=7.1 Hz, 6H, 2×CH3), 1.42 (s, 6H, 2×CH3), 4.24 (q, J=7.1 Hz, 4H, 2×OCH2), 4.29 (s, 4H, 2×OCH2). The organic supernatant was separated concentrated in vacuo The residue was then dissolved in ether rinsed with saturated aqueous sodium carbonate and brine dried over magnesium sulfate filtered concentrated in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diethyl 2,2-bis(hydroxymethyl)malonate (4.4 g, 20 mmol) in CH3CN (50 mL) was added Tf2O (7.1 mL, 11.85 g, 42 mmol) at −20° C., followed by two batches of DIEA (6.45 g, 50 mmol). After 0.5 hr, benzylamine (3.21 g, 35 mmol) was added at −20° C. The mixture was stirred at 70° C. for 2 hr. 100 mL of EA and 100 mL of brine were added. Organic layers were dried over Na2SO4. Purified by chromatography column on silica gel eluting with PE/EA to afford 4.8 g (82%) of diethyl 1-benzylazetidine-3,3-dicarboxylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.34 (m, 2H), 7.22-7.27 (m, 3H), 4.17 (q, J=7.2 Hz, 4H), 3.56 (s, 2H), 3.51 (s, 4H), 2.39 (s, 3H) and 1.17 (t, J=7.2 Hz, 6H). Organic layers were dried over Na2SO4 Purified by chromatography column on silica gel eluting with PE/EA

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diethyl 2,2-bis(hydroxymethyl)malonate (4.4 g, 20 mmol) in CH3CN (50 mL) was added Tf2O (7.1 mL, 11.85 g, 42 mmol) at −20° C., followed by two batches of DIEA (6.45 g, 50 mmol). After 0.5 hr, benzylamine (3.21 g, 35 mmol) was added at −20° C. The mixture was stirred at 70° C. for 2 hr. 100 mL of EA and 100 mL of brine were added. Organic layers were dried over Na2SO4. Purified by chromatography column on silica gel eluting with PE/EA to afford 4.8 g (82%) of diethyl 1-benzylazetidine-3,3-dicarboxylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.34 (m, 2H), 7.22-7.27 (m, 3H), 4.17 (q, J=7.2 Hz, 4H), 3.56 (s, 2H), 3.51 (s, 4H), 2.39 (s, 3H) and 1.17 (t, J=7.2 Hz, 6H). Organic layers were dried over Na2SO4 Purified by chromatography column on silica gel eluting with PE/EA

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

実験手順: Referring to scheme 1, diethyl bis-(hydroxymethyl)malonate (11.5 g, 55 mmol) was treated overnight with 4,4′,4″-trimethoxytrityl chloride (19.2 g, 52 mmol) in pyridine (16 mL) and dioxane (100 mL), and the solvent was evaporated. The residue was dissolved in CH2Cl2 (500 mL), washed with 5% aqueous NaHCO3 (3×100 mL), washed with brine (2×100 mL), dried over Na2SO4 and evaporated. The residue was purified on a silica gel column using a step gradient of ethyl acetate (0 to 15%) in toluene to give 1 (8.2 g, 67.5%) as an oil. HR MALDI MS: calculated for C31H36O9 (M+H+) 553.2442, found 553.2438. 1H NMR (CDCl3) δ 7.29 (6H, d, J=8.8 Hz), 6.83 (6H, d, J=8.8 Hz), 4.26-4.11 (6H, m), 3.80 (9H, s), 3.62 (2H, s), 2.11 (1H, t, J=5.8 Hz), 1.24 (6H, t, J=7.0 Hz). 13C NMR (CDCl3) δ 169.3 (C), 158.5 (C), 136.1 (C), 129.8 (CH), 113.2 (CH), 86.0 (C), 63.7 (CH2), 61.9 (CH2), 61.6 (CH2), 60.6 (C), 55.2 (CH3), 14.1 (CH3). the solvent was evaporated The residue was dissolved in CH2Cl2 (500 mL) washed with 5% aqueous NaHCO3 (3×100 mL) washed with brine (2×100 mL) dried over Na2SO4 evaporated The residue was purified on a silica gel column