1-(2-bromoethoxy)-2-ethoxyethane

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

Procedure: A mixture of 67.5 g(0.5 mole) of N-ethyl-3-methyl-aniline, 98.5 g (0.5 mole) of [β-(β-ethoxy)-ethoxy]ethyl bromide, 44.1 g (0.55 mole) of sodium bicarbonate, 5.50 ml of ethanol and 145 ml of water was refluxed for 80 hours. Ethanol was removed by distillation and the oil layer was extracted with ether. The extract was dried with potassium carbonate and then ether was removed, followed by distillation of the residue oil under reduced pressure. was refluxed for 80 hours Ethanol was removed by distillation the oil layer was extracted with ether The extract was dried with potassium carbonate ether was removed followed by distillation of the residue oil under reduced pressure

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

Procedure: A mixture of 67.5 g(0.5 mole) of N-ethyl-3-methyl-aniline, 98.5 g (0.5 mole) of [β-(β-ethoxy)-ethoxy]ethyl bromide, 44.1 g (0.55 mole) of sodium bicarbonate, 5.50 ml of ethanol and 145 ml of water was refluxed for 80 hours. Ethanol was removed by distillation and the oil layer was extracted with ether. The extract was dried with potassium carbonate and then ether was removed, followed by distillation of the residue oil under reduced pressure. was refluxed for 80 hours Ethanol was removed by distillation the oil layer was extracted with ether The extract was dried with potassium carbonate ether was removed followed by distillation of the residue oil under reduced pressure

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

Procedure: 215 g (1.6 mole) of diethylene glycol monoethyl ether was introduced into a 1 l three-necked flask and slightly warmed by a mantle heater. Then, 135.4 g (0.5 mole) of phosphorus tribromide was slowly added dropwise over a period of 2 hours. The reaction mixture was cooled and poured into 500 cc of water. The desired oily product accumulated at the bottom was extracted with ether and the extract was washed with 100 cc of 10% sulfuric acid two times and with 10% sodium carbonate two times. After further washing with water two times, the extract was dried with potassium carbonate to remove ether, followed by distillation of the residue oil under reduced pressure. After removing the inital fraction of low boiling point, fractions having boiling point of 96° - 98° C/30 mmHg were collected. The yield of (I) was about 40%. slightly warmed by a mantle heater The reaction mixture was cooled bottom was extracted with ether the extract was washed with 100 cc of 10% sulfuric acid two times and with 10% sodium carbonate two times After further washing with water two times the extract was dried with potassium carbonate to remove ether followed by distillation of the residue oil under reduced pressure After removing the inital fraction of low boiling point were collected

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

Procedure: 215 g (1.6 mole) of diethylene glycol monoethyl ether was introduced into a 1 l three-necked flask and slightly warmed by a mantle heater. Then, 135.4 g (0.5 mole) of phosphorus tribromide was slowly added dropwise over a period of 2 hours. The reaction mixture was cooled and poured into 500 cc of water. The desired oily product accumulated at the bottom was extracted with ether and the extract was washed with 100 cc of 10% sulfuric acid two times and with 10% sodium carbonate two times. After further washing with water two times, the extract was dried with potassium carbonate to remove ether, followed by distillation of the residue oil under reduced pressure. After removing the inital fraction of low boiling point, fractions having boiling point of 96° - 98° C/30 mmHg were collected. The yield of (I) was about 40%. slightly warmed by a mantle heater The reaction mixture was cooled bottom was extracted with ether the extract was washed with 100 cc of 10% sulfuric acid two times and with 10% sodium carbonate two times After further washing with water two times the extract was dried with potassium carbonate to remove ether followed by distillation of the residue oil under reduced pressure After removing the inital fraction of low boiling point were collected

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

Procedure: Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) methyl 3-fluoro-4-hydroxybenzoate, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4% ethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 8.55 g of white crystals, 89%, m.p. 33°-36.5° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses. ##STR32## Into a 500-ml, round-bottom flask equipped with a magnetic stirrer heating mantle and condenser under reflux for four hours Three hundred ml of the acetonitrile was then distilled off 300 ml dichloromethane was added The reaction mixture was filtered through Celite the solids were washed thoroughly with dichloromethane Evaporation of the filtrate yielded product in the form of a yellow oil Purification by flash chromatography on silica gel with 4% ethyl ether in dichloromethane followed by low temperature recrystallization from pentane

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

Procedure: Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) methyl 3-fluoro-4-hydroxybenzoate, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4% ethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 8.55 g of white crystals, 89%, m.p. 33°-36.5° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses. ##STR32## Into a 500-ml, round-bottom flask equipped with a magnetic stirrer heating mantle and condenser under reflux for four hours Three hundred ml of the acetonitrile was then distilled off 300 ml dichloromethane was added The reaction mixture was filtered through Celite the solids were washed thoroughly with dichloromethane Evaporation of the filtrate yielded product in the form of a yellow oil Purification by flash chromatography on silica gel with 4% ethyl ether in dichloromethane followed by low temperature recrystallization from pentane

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

Procedure: To 0.975 grams (five millimoles) of 4-hydroxy-4'-cyanobiphenyl dissolved with 1.08 grams (5.5 millimoles) of 1-bromo 2-(2-ethoxyethoxy)-ethane in 25 mls. of acetonitrile, 1.4 grams (ten millimoles) of finely ground potassium carbonate were added. The reaction mixture was refluxed overnight. Thin layer chromatographic analysis indicated total conversion. The reaction mixture was cooled and filtered and the product was washed with acetonitrile and evaporated to a white solid. The product was recrystallized from isopropanol and dried in vacuo to two grams (93% yield) of a compound having the following formula structure: ##STR22## The reaction mixture was refluxed overnight The reaction mixture was cooled filtered the product was washed with acetonitrile evaporated to a white solid The product was recrystallized from isopropanol

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

Procedure: A mixture of 67.5 g(0.5 mole) of N-ethyl-3-methyl-aniline, 98.5 g (0.5 mole) of [β-(β-ethoxy)-ethoxy]ethyl bromide, 44.1 g (0.55 mole) of sodium bicarbonate, 5.50 ml of ethanol and 145 ml of water was refluxed for 80 hours. Ethanol was removed by distillation and the oil layer was extracted with ether. The extract was dried with potassium carbonate and then ether was removed, followed by distillation of the residue oil under reduced pressure. was refluxed for 80 hours Ethanol was removed by distillation the oil layer was extracted with ether The extract was dried with potassium carbonate ether was removed followed by distillation of the residue oil under reduced pressure

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

Procedure: 215 g (1.6 mole) of diethylene glycol monoethyl ether was introduced into a 1 l three-necked flask and slightly warmed by a mantle heater. Then, 135.4 g (0.5 mole) of phosphorus tribromide was slowly added dropwise over a period of 2 hours. The reaction mixture was cooled and poured into 500 cc of water. The desired oily product accumulated at the bottom was extracted with ether and the extract was washed with 100 cc of 10% sulfuric acid two times and with 10% sodium carbonate two times. After further washing with water two times, the extract was dried with potassium carbonate to remove ether, followed by distillation of the residue oil under reduced pressure. After removing the inital fraction of low boiling point, fractions having boiling point of 96° - 98° C/30 mmHg were collected. The yield of (I) was about 40%. slightly warmed by a mantle heater The reaction mixture was cooled bottom was extracted with ether the extract was washed with 100 cc of 10% sulfuric acid two times and with 10% sodium carbonate two times After further washing with water two times the extract was dried with potassium carbonate to remove ether followed by distillation of the residue oil under reduced pressure After removing the inital fraction of low boiling point were collected

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

Procedure: To a stirred solution of (S)-nicotine (0.67 g, 4.1 mmol) in AcOH (20 ml) was added 1-bromo-2-(2-ethoxy-ethoxy)-ethane (1.97 g, 10.0 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.56 g (38%) of (S)-1-[2-(2-ethoxy-ethoxy)-ethyl]-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide (NONB-3O6O) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.65 (1H, d, J=6.0 Hz), 9.26 (1H, s), 8.44 (1H, d, J=7.8 Hz), 7.99 (1H, dd, J=7.8, 6.0 Hz), 5.27 (2H, t, J=4.8 Hz), 4.06 (2H, t, J=4.8 Hz), 3.64 (2H, m), 3.41–3.60 (5H, m), 3.26 (1H, m), 2.43 (2H, m), 2.25 (3H, s), 1.91 (2H, m), 1.60 (1H, m), 1.16 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 145.87, 144.40×2, 144.02, 127.85, 70.83, 69.72, 69.57, 67.17, 66.77, 61.41, 56.91, 40.67, 36.02, 23.41, 15.47; Anal. Calcd for C16H27BrN2.0.5H2O: C, 52.18; H, 7.66; N, 7.61. Found: C, 52.22; H, 7.68; N, 7.50. The mixture was heated at reflux for 3 days AcOH was evaporated the residue was dissolved in CHCl3 The mixture was washed with saturated aqueous NaHCO3, water and brine successively dried Evaporation of the solvent

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

Procedure: To a stirred solution of (S)-nicotine (0.67 g, 4.1 mmol) in AcOH (20 ml) was added 1-bromo-2-(2-ethoxy-ethoxy)-ethane (1.97 g, 10.0 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.56 g (38%) of (S)-1-[2-(2-ethoxy-ethoxy)-ethyl]-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide (NONB-3O6O) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.65 (1H, d, J=6.0 Hz), 9.26 (1H, s), 8.44 (1H, d, J=7.8 Hz), 7.99 (1H, dd, J=7.8, 6.0 Hz), 5.27 (2H, t, J=4.8 Hz), 4.06 (2H, t, J=4.8 Hz), 3.64 (2H, m), 3.41–3.60 (5H, m), 3.26 (1H, m), 2.43 (2H, m), 2.25 (3H, s), 1.91 (2H, m), 1.60 (1H, m), 1.16 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 145.87, 144.40×2, 144.02, 127.85, 70.83, 69.72, 69.57, 67.17, 66.77, 61.41, 56.91, 40.67, 36.02, 23.41, 15.47; Anal. Calcd for C16H27BrN2.0.5H2O: C, 52.18; H, 7.66; N, 7.61. Found: C, 52.22; H, 7.68; N, 7.50. The mixture was heated at reflux for 3 days AcOH was evaporated the residue was dissolved in CHCl3 The mixture was washed with saturated aqueous NaHCO3, water and brine successively dried Evaporation of the solvent

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

Procedure: Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (470 mg, 1.7 mmol) was suspended in dimethylformamide (100 ml). To the suspension were added potassium carbonate (350 mg, 2.5 mmol) and 1-ethoxy-2-(2-bromoethoxy)ethane (505 mg, 2.6 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (147 mg, yield 22%). The solvent was removed in vacuo the residue was purified by silica gel chromatography (1% methanol/chloroform)