3-(dimethylamino)propane-1,2-diol

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: In accordance with Reaction Scheme I, a mixture of 3-(dimethylamino)-1,2-propanediol (1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature under house vacuum (approx. 30 torr) for 0.5 hour. The mixture was heated to 50° C. and stirred for an additional 0.25 hour. The vacuum was removed and the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.). The temperature was increased until the reaction boiled (approximately 140° C.) and the mixture was stirred at reflux for 3 hours. The mixture was diluted with hexane (100 ml) and extracted with water (2×50 ml). The organic layer was concentrated, applied to a column of silica gel (150 g) packed in hexanes in ether (1:2), then eluted with the same solvent mixture to give the title compound (4.5 g) as an oil. In accordance with Reaction Scheme I The mixture was heated to 50° C. stirred for an additional 0.25 hour The vacuum was removed the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.) The temperature was increased until the reaction (approximately 140° C.) the mixture was stirred at reflux for 3 hours The mixture was diluted with hexane (100 ml) extracted with water (2×50 ml) The organic layer was concentrated eluted with the same solvent mixture

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: DOTMA (N-(1-(2,3,-Dioleyloxy(propyl)-N,N,N-trimethylammonium chloride) was prepared as outlined. A mixture of 3-(dimethylamino)-1,2-propanediol (Aldrich Chemical Co., 1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl p-toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature and reduced pressure (30 Torr) for 30 min, and was then heated to 50° C. with stirring for an additional 15 min. The reaction vessel was purged with nitrogen, and the mixture was heated to reflux (approximately 140° C.) for 3 hrs. After cooling, the reaction mixture was diluted with hexane (100 ml), and the resulting solution was extracted with water (2×50 ml). The organic layer was concentrated, and the residue was chromatographed over silica gel by elution with a mixture of hexanes and ether (1:2) to afford the intermediate 2,3-dioleyloxy-1-(dimethylamino)-propane as a colorless oil. Quaternizaton was carried out by condensation of methyl chloride (50 ml) into a Parr pressure apparatus cooled to -78° C. containing this compound (10 g). The sealed vessel was heated behind a safety shield at 70° C. for 48 h. After cooling to 0° C., the reaction vessel was opened, and the excess methyl chloride was allowed to evaporate under a stream of nitrogen in a well-ventilated hood. The crude residue was recrystallized from acetonitrile to afford DOTMA as an off-white solid, mp. 35°-38° C. Full details of the synthesis of DOTMA and analogs will be published elsewhere (Gadek and Felgner, in preparation). was then heated to 50° C. with stirring for an additional 15 min The reaction vessel was purged with nitrogen the mixture was heated to reflux (approximately 140° C.) for 3 hrs After cooling the reaction mixture was diluted with hexane (100 ml) the resulting solution was extracted with water (2×50 ml) The organic layer was concentrated the residue was chromatographed over silica gel by elution with a mixture of hexanes and ether (1:2)

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

Procedure: DOTMA (N-(1-(2,3,-Dioleyloxy(propyl)-N,N,N-trimethylammonium chloride) was prepared as outlined. A mixture of 3-(dimethylamino)-1,2-propanediol (Aldrich Chemical Co., 1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl p-toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature and reduced pressure (30 Torr) for 30 min, and was then heated to 50° C. with stirring for an additional 15 min. The reaction vessel was purged with nitrogen, and the mixture was heated to reflux (approximately 140° C.) for 3 hrs. After cooling, the reaction mixture was diluted with hexane (100 ml), and the resulting solution was extracted with water (2×50 ml). The organic layer was concentrated, and the residue was chromatographed over silica gel by elution with a mixture of hexanes and ether (1:2) to afford the intermediate 2,3-dioleyloxy-1-(dimethylamino)-propane as a colorless oil. Quaternizaton was carried out by condensation of methyl chloride (50 ml) into a Parr pressure apparatus cooled to -78° C. containing this compound (10 g). The sealed vessel was heated behind a safety shield at 70° C. for 48 h. After cooling to 0° C., the reaction vessel was opened, and the excess methyl chloride was allowed to evaporate under a stream of nitrogen in a well-ventilated hood. The crude residue was recrystallized from acetonitrile to afford DOTMA as an off-white solid, mp. 35°-38° C. Full details of the synthesis of DOTMA and analogs will be published elsewhere (Gadek and Felgner, in preparation). was then heated to 50° C. with stirring for an additional 15 min The reaction vessel was purged with nitrogen the mixture was heated to reflux (approximately 140° C.) for 3 hrs After cooling the reaction mixture was diluted with hexane (100 ml) the resulting solution was extracted with water (2×50 ml) The organic layer was concentrated the residue was chromatographed over silica gel by elution with a mixture of hexanes and ether (1:2)

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

Procedure: In accordance with Reaction Scheme I, a mixture of 3-(dimethylamino)-1,2-propanediol (1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature under house vacuum (approx. 30 torr) for 0.5 hour. The mixture was heated to 50° C. and stirred for an additional 0.25 hour. The vacuum was removed and the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.). The temperature was increased until the reaction boiled (approximately 140° C.) and the mixture was stirred at reflux for 3 hours. The mixture was diluted with hexane (100 ml) and extracted with water (2×50 ml). The organic layer was concentrated, applied to a column of silica gel (150 g) packed in hexanes in ether (1:2), then eluted with the same solvent mixture to give the title compound (4.5 g) as an oil. In accordance with Reaction Scheme I The mixture was heated to 50° C. stirred for an additional 0.25 hour The vacuum was removed the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.) The temperature was increased until the reaction (approximately 140° C.) the mixture was stirred at reflux for 3 hours The mixture was diluted with hexane (100 ml) extracted with water (2×50 ml) The organic layer was concentrated eluted with the same solvent mixture

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

Procedure: In accordance with Reaction Scheme I, a mixture of 3-(dimethylamino)-1,2-propanediol (1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature under house vacuum (approx. 30 torr) for 0.5 hour. The mixture was heated to 50° C. and stirred for an additional 0.25 hour. The vacuum was removed and the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.). The temperature was increased until the reaction boiled (approximately 140° C.) and the mixture was stirred at reflux for 3 hours. The mixture was diluted with hexane (100 ml) and extracted with water (2×50 ml). The organic layer was concentrated, applied to a column of silica gel (150 g) packed in hexanes in ether (1:2), then eluted with the same solvent mixture to give the title compound (4.5 g) as an oil. In accordance with Reaction Scheme I The mixture was heated to 50° C. stirred for an additional 0.25 hour The vacuum was removed the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.) The temperature was increased until the reaction (approximately 140° C.) the mixture was stirred at reflux for 3 hours The mixture was diluted with hexane (100 ml) extracted with water (2×50 ml) The organic layer was concentrated eluted with the same solvent mixture

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

Procedure: To a solution of the linoleic acid (25 g, 89.1 mmol) in anhydrous DMF (60 mL), diisopropyl ethylamine (17 mL, 100 mml) was added at room temperature with stirring followed by 3-(dimethylamino)-1,2-propanediol (4.8 g, 40.5 mmol) and EDCI (17.25 g, 89.9 mmol) and the mixture was stirred at room temperature overnight. The TLC of the reaction mixture (eluent 20% EtOAc in hexanes) showed the completion of the reaction. The reaction mixture was poured into ice water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (100 mL), saturated NaHCO3 (100 mL) and dried over Na2SO4. Concentration of the organic layer provided the crude product which was purified by column chromatography (silica gel, eluent: 20% EtOAc in hexanes). The fractions containing pure product was pooled and concentrated. The pure ester was isolated as a clear liquid (5.7 g, 22%). MS m/z 645 (M+H). 1H NMR CDCl3 δ 0.88 (t, J=6.3 Hz, 6H), 1.20-1.39 (m, 28H), 1.61 (t, J=4.9 Hz, 12H), 2.03-2.08 (m, 8H), 2.26-2.38 (m, 10H), 2.44-2.56 (m, 2H), 2.76 (t, J=6.3 Hz, 4H), 4.09 (dd, J=6.1 Hz & 11.9 Hz, 1H), 4.36 (dd, J=3.3 & 11.9 Hz, 1H), 5.29-5.34 (m, 1H), 5.34-5.41 (m, 8H). 13C NMR CDCl3 δ 14.30, 22.79, 25.08, 25.10, 25.83, 27.40, 29.26, 29.30, 29.34, 29.42, 29.55, 29.83, 31.73, 34.32, 34.58, 46.01, 59.37, 64.02, 128.08, 128.24, 130.21, 130.42, 173.39, 173.65. the mixture was stirred at room temperature overnight the completion of the reaction extracted with ethyl acetate (2×100 mL) The combined organic layers were washed with water (100 mL), saturated NaHCO3 (100 mL) dried over Na2SO4 Concentration of the organic layer provided the crude product which was purified by column chromatography (silica gel, eluent: 20% EtOAc in hexanes) The fractions containing pure product concentrated

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

Procedure: In accordance with Reaction Scheme I, a mixture of 3-(dimethylamino)-1,2-propanediol (1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature under house vacuum (approx. 30 torr) for 0.5 hour. The mixture was heated to 50° C. and stirred for an additional 0.25 hour. The vacuum was removed and the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.). The temperature was increased until the reaction boiled (approximately 140° C.) and the mixture was stirred at reflux for 3 hours. The mixture was diluted with hexane (100 ml) and extracted with water (2×50 ml). The organic layer was concentrated, applied to a column of silica gel (150 g) packed in hexanes in ether (1:2), then eluted with the same solvent mixture to give the title compound (4.5 g) as an oil. In accordance with Reaction Scheme I The mixture was heated to 50° C. stirred for an additional 0.25 hour The vacuum was removed the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.) The temperature was increased until the reaction (approximately 140° C.) the mixture was stirred at reflux for 3 hours The mixture was diluted with hexane (100 ml) extracted with water (2×50 ml) The organic layer was concentrated eluted with the same solvent mixture

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

Procedure: In accordance with Reaction Scheme I, a mixture of 3-(dimethylamino)-1,2-propanediol (1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature under house vacuum (approx. 30 torr) for 0.5 hour. The mixture was heated to 50° C. and stirred for an additional 0.25 hour. The vacuum was removed and the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.). The temperature was increased until the reaction boiled (approximately 140° C.) and the mixture was stirred at reflux for 3 hours. The mixture was diluted with hexane (100 ml) and extracted with water (2×50 ml). The organic layer was concentrated, applied to a column of silica gel (150 g) packed in hexanes in ether (1:2), then eluted with the same solvent mixture to give the title compound (4.5 g) as an oil. In accordance with Reaction Scheme I The mixture was heated to 50° C. stirred for an additional 0.25 hour The vacuum was removed the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.) The temperature was increased until the reaction (approximately 140° C.) the mixture was stirred at reflux for 3 hours The mixture was diluted with hexane (100 ml) extracted with water (2×50 ml) The organic layer was concentrated eluted with the same solvent mixture

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

Procedure: A mixture of (2,3-bis-octadec-9-enyloxypropyl)-dimethylamine 4 (378 mg, 0.61 mmol) (synthesised from octadec-9-enyl mesylate and 3-dimethylamino-1,2-propanediol as described previously by Hurley et al., J. Org. Chem., 2004, 69, 980-984) and 3 (335 mg, 1.07 mmol) in acetone (5 ml) was stirred in a sealed-tube at 80° C. for 48 h. After cooling, the solvent was evaporated in vacuo. Purification by flash chromatography on silica (gradient; 5% to 10% methanol in dichloromethane) gave ME42 as an orange oil (140 mg, 27%). After cooling the solvent was evaporated in vacuo Purification by flash chromatography on silica (gradient; 5% to 10% methanol in dichloromethane)