diethyl 2-propylpropanedioate

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:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisobutylaluminum hydride (39.6 mL of a 1.0 M solution in toluene, 39.6 mmol) was added over 5 min to a solution of 2-propyl-malonic acid diethyl ester (4.00 g, 19.8 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (33 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 (1.18 g, 7.46 mmol, 38%). This material was dissolved in ethanol (20 mL) at 25° C. and 4-fluorobenzylamine (0.852 mL, 7.46 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (0.937 g, 14.9 mmol) were added sequentially. The mixture was stirred at 25° C. for 17 h, and then 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; 10-80% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-pentanoic acid ethyl ester (0.703 g, 2.63 mmol, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.1 Hz), 1.29-1.38 (2H, m), 1.44-1.51 (1H, m), 1.57-1.64 (1H, m), 2.57-2.64 (1H, m), 2.68 (1H, dd, J1=4.7 Hz, J2=11.7 Hz), 2.86 (1H, dd, J1=9.2 Hz, J2=11.7 Hz), 3.74 (1H, d, J=14.0 Hz), 3.79 (1H, d, J=13.2 Hz), 4.13-4.18 (2H, m), 6.96-7.01 (2H, m), 7.25-7.29 (2H, m). was quenched with saturated aqueous ammonium chloride (33 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 (1.18 g, 7.46 mmol, 38%) The mixture was stirred at 25° C. for 17 h 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; 10-80% ethyl acetate in hexanes)

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

Procedure: Sodium (0.5 g) was dissolved in ethanol (7 ml) and diethyl propylmalonate (4.4 g) was added to the solution. The resulting mixture was heated under reflux for 15 minutes. To the mixture was added N-(5-bromopentyl)phthalimide (6.4 g) and the mixture was further heated under reflux for 4 hours. Then, ethanol was removed by distillation. The residue was treated with ether and filtered. The filtrate was concentrated and the residue was chromatographed on silica gel column. A fraction eluted with 5% methanol in chloroform was recrystallized from a mixture of ether and hexane to give colorless crystals of diethyl 2-(5-phthalimidopentyl)-2-propylmalonate (m.p. 51°-52° C., yield 3.7 g). The resulting mixture was heated under reflux for 15 minutes the mixture was further heated under reflux for 4 hours Then, ethanol was removed by distillation The residue was treated with ether filtered The filtrate was concentrated the residue was chromatographed on silica gel column A fraction eluted with 5% methanol in chloroform was recrystallized from a mixture of ether and hexane

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium hydride (60% dispersion in mineral oil, 12.6 g, 315 mmol, 1.05 equiv) in DMF (300 mL) at 23° C. was added a solution of diethyl malonate (45.5 mL, 300 mmol, 1 equiv) in DMF (100 mL) via cannula over the course of 10 min. The addition caused a mild exotherm and H2 gas evolution was observed, cooling was not necessary. Following the addition, the reaction was stirred for 45 min at 23° C. then treated with 1-bromopropane (27.3 mL, 300 mmol, 1 equiv). The reaction was stirred at 23° C. for 25 min, then heated to 65° C. for 3 h, then stirred at 23° C. overnight. The reaction mixture was added to 1.0 N HCl (1 L) then extracted with diethyl ether (700 mL). The ether extracts were washed with H2O (400 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to give 65.1 g of product as a clear oil. 13C NMR revealed approximately 4:1 mono to bis-alkylated product ratio. The product diethyl n-propylmalonate was used without further purification: 1H NMR (300 MHz, CDCl3) 4.18 (q, J=6.9 Hz, 4H), 3.32 (t, J=7.8 Hz, 1H), 1.91-1.79 (m, 2H), 1.41-1.25 (m, 2H), 1.25 (t, J=6.9 Hz, 6H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR (300 MHz, CDCl3) (*denotes signal due to minor product of bis-alkylation) 169.6, 61.2, 60.9*, 51.8, 34.4*, 30.7, 20.5, 17.3*, 14.4*, 14.0, 13.7. The addition cooling the addition The reaction was stirred at 23° C. for 25 min heated to 65° C. for 3 h stirred at 23° C. overnight then extracted with diethyl ether (700 mL) The ether extracts were washed with H2O (400 mL), brine (200 mL) dried (MgSO4) filtered concentrated

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium hydride (60% dispersion in mineral oil, 12.6 g, 315 mmol, 1.05 equiv) in DMF (300 mL) at 23° C. was added a solution of diethyl malonate (45.5 mL, 300 mmol, 1 equiv) in DMF (100 mL) via cannula over the course of 10 min. The addition caused a mild exotherm and H2 gas evolution was observed, cooling was not necessary. Following the addition, the reaction was stirred for 45 min at 23° C. then treated with 1-bromopropane (27.3 mL, 300 mmol, 1 equiv). The reaction was stirred at 23° C. for 25 min, then heated to 65° C. for 3 h, then stirred at 23° C. overnight. The reaction mixture was added to 1.0 N HCl (1 L) then extracted with diethyl ether (700 mL). The ether extracts were washed with H2O (400 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to give 65.1 g of product as a clear oil. 13C NMR revealed approximately 4:1 mono to bis-alkylated product ratio. The product diethyl n-propylmalonate was used without further purification: 1H NMR (300 MHz, CDCl3) 4.18 (q, J=6.9 Hz, 4H), 3.32 (t, J=7.8 Hz, 1H), 1.91-1.79 (m, 2H), 1.41-1.25 (m, 2H), 1.25 (t, J=6.9 Hz, 6H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR (300 MHz, CDCl3) (*denotes signal due to minor product of bis-alkylation) 169.6, 61.2, 60.9*, 51.8, 34.4*, 30.7, 20.5, 17.3*, 14.4*, 14.0, 13.7. The addition cooling the addition The reaction was stirred at 23° C. for 25 min heated to 65° C. for 3 h stirred at 23° C. overnight then extracted with diethyl ether (700 mL) The ether extracts were washed with H2O (400 mL), brine (200 mL) dried (MgSO4) filtered concentrated

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

Procedure: To a suspension of sodium hydride (1.3 g) in dimethylformamide (15 ml), a solution of diethyl propylmalonate (6.6 g) in dimethylformamide (45 ml) was added under ice-cooling and the mixture was stirred at room temperature for an hour. To the solution was added a solution of 2-(2-benzyloxyphenyl)ethyl iodide (10 g) in dimethylformamide (30 ml), the mixture was stirred at the same temperature for an hour and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=8:1) to give the subject compound (10 g). cooling the mixture was stirred at the same temperature for an hour left extracted with ethyl acetate The organic layer was washed with an aqueous sodium hydrogencarbonate solution a saturated brine and dried over magnesium sulfate The solvent was distilled away under reduced pressure

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

Procedure: 2-Cyano-2-propyl-6-methoxy-trans-decalin is obtained analogously from 2-(2-bromoethyl-4-methoxycyclohexylmethyl)-valeronitrile (obtainable by chloromethylation of 2-(m-methoxyphenyl)-ethanol to give 2-(2-chloromethyl-5-methoxyphenyl)-ethanol, reaction with diethyl propylmalonate, hydrolysis and decarboxylation to give 2-[2-(2-hydroxyethyl)-4-methoxybenzyl]-valeric acid, hydrogenation to 2-[2-(2-hydroxyethyl)-4-methoxycyclohexylmethyl]-valeric acid, conversion into the amide, reaction with SOBr2 to give 2-(2-bromoethyl-4-methoxy-cyclohexylmethyl)-valeramide and dehydration). to give

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

Procedure: To a suspension of sodium hydride (1.3 g) in dimethylformamide (15 ml), a solution of diethyl propylmalonate (6.6 g) in dimethylformamide (45 ml) was added under ice-cooling and the mixture was stirred at room temperature for an hour. To the solution was added a solution of 2-(2-benzyloxyphenyl)ethyl iodide (10 g) in dimethylformamide (30 ml), the mixture was stirred at the same temperature for an hour and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=8:1) to give the subject compound (10 g). cooling the mixture was stirred at the same temperature for an hour left extracted with ethyl acetate The organic layer was washed with an aqueous sodium hydrogencarbonate solution a saturated brine and dried over magnesium sulfate The solvent was distilled away under reduced pressure

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

Procedure: TLC analysis: Silica gel 60 F254 on aluminum sheet. Eluent is mixture from petroleum ether with diethyl ether (9:1 v/v). Chromatogram is sprinkled by indicator spray and then is charred at 150° C. Composition of indicator spray: 4-methoxybenzaldehyde (10 ml), ethanol (200 ml), 98% H2SO4 (10 ml) and glacial acetic acid (2 ml). One spot. Rf 0.54. is charred at 150° C

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisobutylaluminum hydride (39.6 mL of a 1.0 M solution in toluene, 39.6 mmol) was added over 5 min to a solution of 2-propyl-malonic acid diethyl ester (4.00 g, 19.8 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (33 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 (1.18 g, 7.46 mmol, 38%). This material was dissolved in ethanol (20 mL) at 25° C. and 4-fluorobenzylamine (0.852 mL, 7.46 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (0.937 g, 14.9 mmol) were added sequentially. The mixture was stirred at 25° C. for 17 h, and then 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; 10-80% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-pentanoic acid ethyl ester (0.703 g, 2.63 mmol, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.1 Hz), 1.29-1.38 (2H, m), 1.44-1.51 (1H, m), 1.57-1.64 (1H, m), 2.57-2.64 (1H, m), 2.68 (1H, dd, J1=4.7 Hz, J2=11.7 Hz), 2.86 (1H, dd, J1=9.2 Hz, J2=11.7 Hz), 3.74 (1H, d, J=14.0 Hz), 3.79 (1H, d, J=13.2 Hz), 4.13-4.18 (2H, m), 6.96-7.01 (2H, m), 7.25-7.29 (2H, m). was quenched with saturated aqueous ammonium chloride (33 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 (1.18 g, 7.46 mmol, 38%) The mixture was stirred at 25° C. for 17 h 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; 10-80% ethyl acetate in hexanes)