TETRAHYDRO-3-(IODOMETHYL)-FURAN

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (0.84 mL, 5.98 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (2.29 mL, 5.72 mmol). The reaction mixture was stirred at −78° C. for 15 min. At this time, the reaction was slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 1.20 g, 5.20 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL). The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 3-iodomethyl-tetrahydro-furan (2.21 g, 10.4 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.69 mL) and tetrahydrofuran (5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate 3×30 mL). The organic layers were then combined and washed with a 10% aqueous sulfuric acid solution (25 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 41%) as a light yellow oil: EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743. found 314.0729. to stir at −78° C. for 1 h to warm to 25° C. where it was stirred for 48 h The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) extracted with ethyl acetate 3×30 mL) washed with a 10% aqueous sulfuric acid solution (25 mL) The combined organic layers were then dried over sodium sulfate filtered concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a round bottom flask was placed tetrahydrofuran (20 mL) and 1,1,1,3,3,3-hexamethyldisilazane (0.97 mL, 4.66 mmol) and it was cooled to −78° C. in a dry ice/acetone bath. To this cooled solution was then added n-butyl lithium (2.5 M solution in hexanes, 1.75 mL, 4.37 mmol) and it was stirred for 15 min at −78° C. To this was then added a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in PCT WO 2003/095438 A1, Example 4, 0.96 g, 4.16 mmol) in tetrahydrofuran (6 mL) dropwise. The reaction was then stirred for 15 min at −78° C. then at 0° C. for 1 h which resulted in a yellow solution. After such time, the reaction was cooled back to −78° C. and a solution of 3-iodomethyl-tetrahydro-furan (1.32 g, 6.23 mmol) in tetrahydrofuran (6 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL, 6.24 mmol) was added dropwise at −78° C. The reaction was stirred at −78° C. for 15 min, at 0° C. for 2.5 h and then was stored in a freezer overnight. After such time, the reaction was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated sodium chloride solution wash. The organics were dried over sodium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (120 g column, 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (1.0 g, 77%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.42-1.62 (m, 1H, CH of CH2), 1.79-1.94 (m, 1H, CH of CH2), 1.94-2.21 (m, 3H, CH and CH2), 2.47 (s, 3H, SCH3), 3.26-3.38 (m, 1H, OCH of OCH2), 3.45-3.52 (m, 1H, ArCH), 3.65-3.75 (m, 1H, OCH of OCH2), 3.67 (s, 3H, OCH3), 3.76-3.94 (m, 2H, 2×OCH of OCH2), 7.11 (d, Jo=8.2 Hz, 1H, Ar), 7.19 (dd, Jo=8.2 Hz, Jm=1.7 Hz, 1H, Ar), 7.30 (d, Jm=1.7 Hz, 1H, Ar). In a round bottom flask was placed at 0° C. for 1 h which resulted in a yellow solution After such time, the reaction was cooled back to −78° C. The reaction was stirred at −78° C. for 15 min, at 0° C. for 2.5 h was stored in a freezer overnight washed with a saturated aqueous ammonium chloride solution wash The organics were dried over sodium sulfate filtered concentrated in vacuo Purification on an AnaLogix Intelliflash system (120 g column, 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes)

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (0.84 mL, 5.98 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (2.29 mL, 5.72 mmol). The reaction mixture was stirred at −78° C. for 15 min. At this time, the reaction was slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 1.20 g, 5.20 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL). The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 3-iodomethyl-tetrahydro-furan (2.21 g, 10.4 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.69 mL) and tetrahydrofuran (5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were then combined and washed with a 10% aqueous sulfuric acid solution (25 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 41%) as a light yellow oil: EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743, found 314.0729. to stir at −78° C. for 1 h to warm to 25° C. where it was stirred for 48 h The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) extracted with ethyl acetate (3×30 mL) washed with a 10% aqueous sulfuric acid solution (25 mL) The combined organic layers were then dried over sodium sulfate filtered concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (0.84 mL, 5.98 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (2.29 mL, 5.72 mmol). The reaction mixture was stirred at −78° C. for 15 min. At this time, the reaction was slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 1.20 g, 5.20 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL). The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 3-iodomethyl-tetrahydro-furan (2.21 g, 10.4 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.69 mL) and tetrahydrofuran (5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were then combined and washed with a 10% aqueous sulfuric acid solution (25 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 41%) as a light yellow oil: EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743, found 314.0729. to stir at −78° C. for 1 h to warm to 25° C. where it was stirred for 48 h The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) extracted with ethyl acetate (3×30 mL) washed with a 10% aqueous sulfuric acid solution (25 mL) The combined organic layers were then dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of 3-(iodomethyl)tetrahydrofuran (10.1 g) in acetonitrile (101 mL) was added triphenylphosphine (13.1 g), followed by heating under reflux for 1 week. The solution was concentrated under reduced pressure, followed by addition of diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to obtain triphenyl(tetrahydrofuran-3-ylmethyl)phosphonium iodide (18.8 g) as a white solid. by heating under reflux for 1 week The solution was concentrated under reduced pressure followed by addition of diethyl ether The resulting solid was collected by filtration washed with diethyl ether

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-cyclopent-2-enone (285 mg, 0.89 mmol) in anhydrous tetrahydrofuran (6 ml) at −78° C. under an atmosphere of nitrogen is added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 0.55 ml, 1.0 mmol) dropwise over a period of 5 minutes and the reaction allowed to stir at −78° C. for 30 minutes. A solution of 3-iodomethyl tetrahydrofuran (212 mg, 1 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 5 minutes before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic later separated, dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-5-(tetrahydro-furan-3-ylmethyl)-cyclopent-2-enone (150 mg) to warm to room temperature stirred for a further 30 minutes The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) extracted with ethyl acetate (50 ml) the organic later separated dry loaded onto silica purified by flash chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (210 mg, 0.670 mmol) was suspended in dimethylformamide (6.0 ml), added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl), and stirred overnight at 80° C. The reaction solution was further added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl) and stirred overnight at 80° C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2→100:5, v/v) to obtain the title compound (277 mg, quantitative). stirred overnight at 80° C The reaction mixture was concentrated the residue was purified by silica gel column chromatography (chloroform

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (E)-2-{2-Hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-1-ethenylcyanide (100 mg) was added with dimethylformamide (5 ml), diisopropylethylamine (500 ml) and 3-(iodomethyl)tetrahydrofuran (200 ml), and then the mixture was stirred at 80° C. for 2 hours and further stirred overnight at room temperature. After the reaction mixture was distributed between chloroform and water, the organic layer was dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (51 mg). further stirred overnight at room temperature the organic layer was dried over magnesium sulfate After the solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography