diethyl 2-(2-methylpropyl)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:

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

実験手順: Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-isobutyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 4 h, and then was quenched with saturated aqueous ammonium chloride (35 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.20 g, 12.8 mmol, 73%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.46 mL, 12.8 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.61 g, 25.6 mmol) were added sequentially. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-4-methyl-pentanoic acid ethyl ester (0.995 g, 3.54 mmol, 28%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (3H, d, J=6.2 Hz), 0.91 (3H, d, J=6.0 Hz), 1.26 (3H, t, J=7.0 Hz), 1.54-1.61 (1H, m), 2.63-2.68 (2H, m), 2.83 (1H, dd, J1=10.2 Hz, J2=12.2 Hz), 3.72 (1H, d, J=13.3 Hz), 3.77 (1H, d, J=13.2 Hz), 4.13-4.18 (2H, m), 6.96-7.00 (2H, m), 7.23-7.27 (2H, m). was quenched with saturated aqueous ammonium chloride (35 mL) The cold bath was removed 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL) The organic layer was dried over sodium sulfate was concentrated in vacuo to afford crude product (2.20 g, 12.8 mmol, 73%) The mixture was stirred at 25° C. for 18 h was concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-70% ethyl acetate in hexanes)

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

実験手順: To a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g, 0.57 mol) over 20 min. at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to 25° C. The reaction mixture was cooled down to 0° C. again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31 mol) in DMF (150 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. After cooling, the reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL), and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil. The crude product (92.0 g, 82%) was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.70 (dd, J=12.9, 1.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.25-4.18 (m, 4H), 2.28 (d, J=6.3 Hz, 2H), 1.54-1.45 (m, 1H), 1.25 (t, J=7.0 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 169.2, 154.5 (d, 1JCF=263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1 (d, 3JCF=3.6 Hz), 118.6 (d, 2JCF=23.3 Hz), 62.0, 60.3, 44.1, 24.7, 23.6, 13.9. warmed to 25° C The reaction mixture was cooled down to 0° C. again The reaction mixture was stirred at 25° C. for 16 h After cooling extracted with EtOAc (3×100 mL) The combined organic phases washed with water (3×100 mL), brine (100 mL) dried (MgSO4) Evaporation of the solvent under reduced pressure gave a brown oil The crude product (92.0 g, 82%) was used for the next step without purification

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

実験手順: To a solution of diethyl isobutylmalonate (50.0 g, 231 mmol) in anhydrous DMF (200 mL) cooled in an ice bath was added NaH (60%, 11.1 g, 277 mmol) in small portions. After the addition, the reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. 5-Chloro-2-nitrobenzotrifluoride (47.3 g, 210 mmol) in anhydrous DMF (50 mL) was added dropwise and the mixture was stirred at room temperature for two days. The DMF was removed under high vacuum and the residue was diluted with ethyl acetate (400 mL). Water (400 mL) was added dropwise; ammonium chloride (25 g) was added and the layers were separated. The organic layer was washed with brine (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a red-brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (12:1) to give the desired product diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 87%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.94 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 4.25 (m, 4H), 2.33 (d, 2H, J=6.6 Hz), 1.51 (m, 1H), 1.26 (t, 6H, J=7.2 Hz), 0.84 (d, 6H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 169.23, 146.71, 142.86, 132.94, 127.94 (q, J=5 Hz), 124.55, 123.12 (q, J=33 Hz), 121.79 (q, J=272 Hz), 62.19, 61.59, 44.16, 24.66, 23.66, 13.89. After the addition at room temperature for 30 min the mixture was stirred at room temperature for two days The DMF was removed under high vacuum the residue was diluted with ethyl acetate (400 mL) Water (400 mL) was added dropwise ammonium chloride (25 g) was added the layers were separated The organic layer was washed with brine (400 mL) dried over sodium sulfate concentrated under reduced pressure to give a red-brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (12:1)

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

実験手順: 2-Isobutylmalonic acid diethyl ester (40.0 g, 0.185 mol) in DMF (50 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 8.0 g, 0.33 mol) in 200 mL DMF (200 mL) over 20 min. at 0° C. under nitrogen. The mixture was stirred for 0.5 h at room temperature, cooled to 0° C. and 1,2,4-trifluoro-5-nitro-benzene (30.0 g, 169.5 mmol) in DMF (150 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc, gradient) to give 57.0 g (90%) of 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester as yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.87 (dd, J=12.3, 6.0 Hz, 1H), 7.79 (dd, J=10.1, 6.4 Hz, 1H), 4.30-4.18 (m, 4H), 2.27 (d, J=5.8 Hz, 2H), 1.60-1.50 (m, 1H), 1.26 (t, J=7.1 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 168.2, 155.1 (d, 1JCF=252.3 Hz), 150.9 (d, 1JCF=263.2 Hz), 135.7, 135.1, 120.0 (dd, 2JCF=26.0, 3JCF=4.0 Hz), 113.0 (d, 2JCF=29.0 Hz), 62.3, 43.1, 24.9, 23.8, 13.8. cooled to 0° C. The resulting reaction mixture was stirred at room temperature for 16 h extracted with EtOAc (3×100 mL) The combined organic phases were washed with water (3×100 mL), brine (100 mL) dried (MgSO4) Evaporation of solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc, gradient)

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

実験手順: 2-Cyclohexyl-2-hydroxymethylpropan-1,3-diol and 2-isobutyl-2-hydroxymethylpropan-1,3-diol were prepared from diethyl cyclohexylmalonate and diethyl i-butylmalonate respectively in a manner analogous to the synthesis of 2-(2,2-dimethylpropyl)-2-hydroxymethylpropane-1,3-diol (example 5).

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

実験手順: 2-Cyclohexyl-2-hydroxymethylpropan-1,3-diol and 2-isobutyl-2-hydroxymethylpropan-1,3-diol were prepared from diethyl cyclohexylmalonate and diethyl i-butylmalonate respectively in a manner analogous to the synthesis of 2-(2,2-dimethylpropyl)-2-hydroxymethylpropane-1,3-diol (example 5).

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

実験手順: 2-Cyclohexyl-2-hydroxymethylpropan-1,3-diol and 2-isobutyl-2-hydroxymethylpropan-1,3-diol were prepared from diethyl cyclohexylmalonate and diethyl i-butylmalonate respectively in a manner analogous to the synthesis of 2-(2,2-dimethylpropyl)-2-hydroxymethylpropane-1,3-diol (example 5).

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

実験手順: Ethyl 2-(ethoxycarbonyl)-4-(methyl)pentanoate (6 g., 28 mM) was dissolved in ethanol (9 ml.) and 4 N-aqueous sodium hydroxide (7 ml.) was added. The mixture was stirred at ambient temperature for 1 hour and then evaporated. The residue was diluted with water (30 ml.) and the aqueous solution was washed with diethyl ether (3×10 ml.). The combined ethereal washings were backextracted with water (5 ml.). The combined aqueous phases were acidified to pH 3 at 0° C. with citric acid, and the resulting oil was extracted into ethyl acetate (4×20 ml.). The combined extracts were washed with water (2×20 ml.) and dried (MgSO4). The mixture was filtered and the solvent was evaporated to give 2-ethoxycarbonyl-4-methylpentanoic acid as an oil. The structure was confirmed by NMR. evaporated The residue was diluted with water (30 ml.) the aqueous solution was washed with diethyl ether (3×10 ml.) were acidified to pH 3 at 0° C. with citric acid the resulting oil was extracted into ethyl acetate (4×20 ml.) The combined extracts were washed with water (2×20 ml.) dried (MgSO4) The mixture was filtered the solvent was evaporated

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

実験手順: Diethyl isobutylmalonate (22.0 g.) was added to a stirred suspension of sodium hydride (4.8 g. 50% dispersion in oil) in dry toluene (200 ml.), under nitrogen. The mixture was stirred at 80° for one hour. The mixture was cooled and benzyl chloromethyl thioether 5 (16.0 g.) in dry toluene (50 ml.) was added and the mixture was stirred at 80° for two hours. The mixture was cooled and poured into water. The aqueous mixture was extracted into diethyl ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Diethyl 2-benzylthiomethyl-2-isobutylmalonate (32.0 g.) was obtained as a yellow oil and was used without further purification. The mixture was cooled the mixture was stirred at 80° for two hours The mixture was cooled The aqueous mixture was extracted into diethyl ether The ether extracts were washed with water dried over anhydrous magnesium sulphate evaporated in vacuo