6-bromohex-1-ene

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 31.5 g, 1.28 eq.) was slowly added under nitrogen atmosphere to a solution of N-methyl-2,2,2-trifluoroacetamide (100 g, 1.28 eq.) in DMF (500 mL) at 0° C. The reaction mixture was stirred for 90 min at 0° C., and then 6-bromo-1-hexene (100 g, 1 eq.) was added dropwise over 45 min. The reaction mixture was allowed to warm up to room temperature, and stirred for 3 days at room temperature. The reaction mixture was then poured into water and extracted tree time with EtOAc. The combined organics layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to produce compound 31a as colorless oil in 56% yield. to warm up to room temperature stirred for 3 days at room temperature extracted tree time with EtOAc The combined organics layers were dried over anhydrous sodium sulphate concentrated under reduced pressure The residue was purified by flash chromatography on silica gel

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

Procedure: 3-(5,6-Oxidohexyl)-1-methylthymine was synthesized as follows: A mixture of sodium hydride (343 mg, 14 mmol) and 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (30 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (2.30 g, 14 mmol) was added. After stirring for 69 hours, the reaction mixture was poured into water (100 ml) and extracted with dichloromethane (4×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (40 ml), dried over sodium sulfate, and then the solvent was evaporated under vacuum to give a residue which was recrystallized (dichloromethane-ethyl ether) to give 3-(5-hexenyl)-1-methylthymine (2.80 g, 88% yield). After stirring for 69 hours extracted with dichloromethane (4×50 ml) The combined organic layers were washed with saturated aqueous sodium chloride solution (40 ml) dried over sodium sulfate the solvent was evaporated under vacuum to give a residue which was recrystallized (dichloromethane-ethyl ether)

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

Procedure: 3-(5,6-Oxidohexyl)-1-methyluracil was synthesized as follows: A mixture of sodium hydride (86 mg, 3.6 mmol) and 1-methyluracil (500 mg, 4 mmol) in dimethyl sulfoxide (25 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (647 mg, 4 mmol) was added. After stirring for 20 hours, the reaction mixture was poured into water (50 ml) and extracted with 20% ethanol-dichloromethane (3×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml) and dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue which was purified by column chromatography (silica, ethyl acetate) to give 3-(5-hexenyl)-1-methyluracil (598 mg, 72% yield). After stirring for 20 hours extracted with 20% ethanol-dichloromethane (3×50 ml) The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml) dried over sodium sulfate The solvent was evaporated under vacuum to give a residue which was purified by column chromatography (silica, ethyl acetate)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 0° C. and under nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 31.5 g, 1.28 eq.) was slowly added to a cooled solution of N-methyl-2,2,2-trifluoroacetamide (100 g, 1.28 eq.) in DMF (500 mL). The reaction mixture was stirred for 2 hrs at 0° C. and 6-bromo-1-hexene (100 g, 1 eq.) was added dropwise for 45 min. The reaction mixture was allowed to warm up to room temperature and was stirred for 3 days. The reaction mixture was poured into water and extracted three times with EtOAc. The combined organic layers were dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 1a as colourless oil in 56% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.27-1.38 (m, 2H), 1.48-1.60 (m, 2H), 2-2.06 (m, 2H), 2.93 (m, 3H), 3.35-3.40 (m, 2H), 4.92-5.04 (m, 2H), 5.73-5.83 (m, 1H). to warm up to room temperature was stirred for 3 days extracted three times with EtOAc The combined organic layers were dried over anhydrous sodium sulphate evaporated under reduced pressure The resulting residue was purified by chromatography on silica gel (petroleum ether/EtOAc)

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

Procedure: 1-(5,6-Oxidohexyl)-3,7-dimethylxanthine was synthesized and used as an intermediate for synthesizing inventive compounds nos. 1517 and 1595 as described in examples 2 and 3 below. A mixture of l-bromo-5-hexene (10.7 g, 66 mmol), sodium hydride (1.58 g, 66 mmol), and 3,7-dimethylxanthine (11.9 g, 66 mmol) in dimethylsulfoxide (100 ml) was stirred for 43 hr. The solution was treated with water (200 ml) and then extracted with dichloromethane (3×80 ml). The combined extracts were washed with water (3×100 ml), dried over magnesium sulfate, and then the solvent was evaporated under vacuum to give 1-(5-hexenyl)-3,7-dimethylxanthine (17 g, 98% yield) as a white powder. used as an intermediate for synthesizing inventive compounds nos extracted with dichloromethane (3×80 ml) The combined extracts were washed with water (3×100 ml) dried over magnesium sulfate the solvent was evaporated under vacuum

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

Procedure: As per the procedure of Example 49, uridine (10.5 g) was treated with dibutyl tin oxide (10.5 g, 1 eq). The resulting 2',3'-O-dibutylstannyleneuridine was treated with 6-bromohexene (3.5 ml, 1.2 eq.) and sodium iodide (3.3 g, 1.0 eq.) at 115° C. as per Example 50 to give the 2' and 3' isomers (3.3 g) as a foam. to give the 2' and 3' isomers (3.3 g) as a foam

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

Procedure: This example illustrates a synthesis of 3-(5,6-Oxidohexyl)-1-methylthymine (inventive compound no. 1906). Sodium hydride (343 mg, 14 mmol) was added to a stirring solution of 1-methylthymine (Sigma, 2.00 g, 14 mmol) in dimethylsulfoxide (30 mL). After 15 minutes, 6-bromo-1-hexene (Lancaster, 2.30 g, 14 mmol) was added and stirring continued for 69 hours. The reaction mixture was then poured into water (100 mL) and extracted with dichloromethane (4×50 mL). The combined organic layers were washed with saturated aqueous salt solution (40 mL) and dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue which was crystallized in dichloromethane/ethyl ether to yield 2.80 g (88% yield) 3-(5-hexenyl)-1-methylthymine (inventive compound no. 1905). continued for 69 hours extracted with dichloromethane (4×50 mL) The combined organic layers were washed with saturated aqueous salt solution (40 mL) dried over sodium sulfate The solvent was evaporated under vacuum to give a residue which was crystallized in dichloromethane/ethyl ether

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

Procedure: This example illustrates a synthesis of 3-(5,6-Oxidohexyl)-1-methyluracil (inventive compound no. 1808). Sodium hydride (86 mg, 3.6 mmol) was added to a stirring solution of 1-methyluracil (500 mg, 4 mmol) in dimethyl sulfoxide (25 mL). After 15 minutes, 6-bromo-1-hexene (647 mg, 4 mmol) was added and the mixture stirred further for 20 hours. The reaction mixture was then poured into water (50 mL) and extracted with 20% ethanol/dichloromethane (3×50 mL). The combined organic layers were washed with aqueous saturated salt solution (20 mL) and dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue which was purified by chromatography with silica and ethyl acetate to yield 598 g (72% yield) of 3-hexenyl-1-methyluracil (inventive compound no. 1800). extracted with 20% ethanol/dichloromethane (3×50 mL) The combined organic layers were washed with aqueous saturated salt solution (20 mL) dried over sodium sulfate The solvent was evaporated under vacuum to give a residue which was purified by chromatography with silica and ethyl acetate

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

Procedure: Sodium hydride (86 mg, 3.6 mmol) was added to a stirring solution of 3-methyl-7-(methylpivaloyl)xanthine 1404 (1.00 g, 3.6 mmol) in dimethyl sulfoxide (25 mL). After 15 minutes, 6-bromo-1-hexene (589 mg, 3.6 mmol) was added and stirring continued for 72 hours. The reaction mixture was then poured into water (70 mL) and extracted with dichloromethane (2×100 mL) and 20% ethanol/dichloromethane (1×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL) and dried over magnesium sulfate. The solvent was evaporated under vacuum to give a thick oil. Chromotograpy of the resulting thick oil using silica and ethyl acetate yielded 870 mg (67% yield) 1-(5-hexenyl)-3-methyl-7-(methylpivaloyl)xanthine (inventive compound no. 1441) continued for 72 hours extracted with dichloromethane (2×100 mL) and 20% ethanol/dichloromethane (1×100 mL) The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL) dried over magnesium sulfate The solvent was evaporated under vacuum to give a thick oil