O-phenyl chloromethanethioate

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:0.00; 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: To a solution of 1-(3,5-di-O-benzoyl-β-L-arabinofuranosyl)uracil 12 (5.2 g, 11.4 mmoL) in anhydrous 1,2-dichloroethane (120 mL) were added phenoxythiocarbonyl chloride (4.7 mL, 34.3 mL) and 4-(dimethylamino)pyridine (DMAP, 12.5 g, 102.6 mmoL). The resulting solution was stirred at room temperature under argon atmosphere for 1 h and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and the organic solution was successively washed with an ice-cold 0.2 N hydrochloric acid solution (3×200 mL) and water (2×200 mL), dried over Na2SO4 then evaporated under reduced pressure. The crude material was co-evaporated several times with anhydrous dioxane and dissolved in this solvent (110 mL). To the resulting solution were added under argon tris-(trimethylsilyl)silane hydride (4.2 mL, 13.7 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.6 g, 3.76 mmol). The reaction mixture was heated and stirred at 100° C. for 1 h under argon, then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-5%)] to give 13 (2.78 g, 56%) which was crystallized from EtOH: mp=223-225° C.; H-NMR (DMSO-d6): δ 11.4 (br s, 1H, NH), 8.0-7.5 (m, 11H, 2CH6H5CO, H-6), 6.28 (t, 1H, H-1′, J=7 Hz), 5.5 (m, 2H, H-1′ and H-5), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 2H, H-2′ and H-2″); MS: FAB>0 (matrix GT) m/z 437 (M+H)+, 3325 (S)+; FAB<0 (matrix GT) m/z 435 (M−H)−, 111 (B)−; Anal. Calcd for C23H20N2O7: C, 63.30; H, 4.62; N, 6.42. Found: C, 62.98; H, 4.79; N, 6.40. evaporated under reduced pressure The residue was dissolved in dichloromethane (300 mL) the organic solution was successively washed with an ice-cold 0.2 N hydrochloric acid solution (3×200 mL) and water (2×200 mL) dried over Na2SO4 then evaporated under reduced pressure dissolved in this solvent (110 mL) To the resulting solution were added under argon tris-(trimethylsilyl)silane hydride (4.2 mL, 13.7 mmol) The reaction mixture was heated stirred at 100° C. for 1 h under argon cooled to room temperature evaporated under reduced pressure The residue was purified by silica gel column chromatography [eluent

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

Procedure: To a solution of compound 3 (1.00 g, 2.11 mmol) in dry acetonitrile (65 mL) were added 4-(dimethylamino)pyridine (0.77 g, 6.32 mmol) and phenoxythiocarbonyl chloride (0.44 mL, 3.16 mmol). The mixture was stirred at room temperature for 2 h. After concentration, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (2×30 mL), aqueous solution of hydrochloric acid 0.5 N (30 mL) and water (3×30 mL). The organic layer was dried, filtered and concentrated to dryness. The crude thiocarbonylated intermediate was directly treated with tris-(trimethylsilyl)silane hydride (0.78 mL, 5.23 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.112 g, 0.69 mmol) in dry dioxane (17 mL) at reflux for 2 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane) to give pure 4 (0.93 g, 96%) as a foam: 1H NMR (DMSO-d6): δ 2.9-3.1 (m, 2H, H-2′ and H-2″), 4.6-4.7 (m, 3H, H-4′, H-5′ and H-5″), 5.8 (br s, 1H, H-3′), 6.43 (dd, 1H, H-1′, J1′,2′=3.1 Hz, J1′,2″=7.6 Hz), 7.3 (br s, 2H, NH2-6), 7.4-7.9 (m, 10H, 2 benzoyls), 8.05 and 8.33 (2s, 2H, H-2 and H-8); ms : matrix G/T, (FAB+) m/z 460 [M+H]+, 325 [S]+, 136 [BH2]+, (FAB−) m/z 458 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 261 mn (ε 14400), 231 nm (ε 26300), λmin 249 nm (ε 12000); [α]D20=−38 (c 1.04, DMSO). After concentration the residue was dissolved in dichloromethane (50 mL) washed successively with water (2×30 mL), aqueous solution of hydrochloric acid 0.5 N (30 mL) and water (3×30 mL) The organic layer was dried filtered concentrated to dryness at reflux for 2 h The solvent was removed under vacuum the residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(3,5-di-O-benzoyl-β-L-arabinofuranosyl)uracil 12 (5.2 g, 11.4 mmoL) in anhydrous 1,2-dichloroethane (120 mL) were added phenoxythiocarbonyl chloride (4.7 mL, 34.3 mL) and 4-(dimethylamino)pyridine (DMAP, 12.5 g, 102.6 mmoL). The resulting solution was stirred at room temperature under argon atmosphere for 1h and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and the organic solution was successively washed with an ice-cold 0.2 N hydrochloric acid solution (3×200 mL) and water (2×200 mL), dried over Na2SO4 then evaporated under reduced pressure. The crude material was co-evaporated several times with anhydrous dioxane and dissolved in this solvent (110 mL). To the resulting solution were added under argon tris-(trimethylsilyl)silane hydride (4.2 mL, 13.7 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.6 g, 3.76 mmol). The reaction mixture was heated and stirred at 100° C. for 1 h under argon, then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-5%)] to give 13 (2.78 g, 56%) which was crystallized from EtOH: mp=223-225° C.; H-NMR (DMSO-d6):δ 11.4 (br s, 1H, NH), 8.0-7.5 (m, 11H, 2 C6H5CO, H-6), 6.28 (t, 1H, H-1′, J=7 Hz), 5.5 (m, 2H, H-1′ and H-5), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 2H, H-2′ and H-2″); MS: FAB>0 (matrix GT) m/z 437 (M+H)+, 3325 (S)+; FAB<0 (matrix GT) m/z 435 (M—H)—, 111 (B)—; Anal. Calcd for C23H20N2O7: C, 63.30; H, 4.62; N, 6.42. Found: C, 62.98 ; H, 4.79 ; N, 6.40. evaporated under reduced pressure The residue was dissolved in dichloromethane (300 mL) the organic solution was successively washed with an ice-cold 0.2 N hydrochloric acid solution (3×200 mL) and water (2×200 mL) dried over Na2SO4 then evaporated under reduced pressure dissolved in this solvent (110 mL) To the resulting solution were added under argon tris-(trimethylsilyl)silane hydride (4.2 mL, 13.7 mmol) The reaction mixture was heated cooled to room temperature evaporated under reduced pressure The residue was purified by silica gel column chromatography [eluent

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

Procedure: To a solution of compound 3 (1.00 g, 2.11 mmol) in dry acetonitrile (65 niL) were added 4-(dimethylamino)pyridine (0.77 g, 6.32 mmol) and phenoxythiocarbonyl chloride (0.44 mL, 3.16 mmol). The mixture was stirred at room temperature for 2 h. After concentration, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (2×30 mL), aqueous solution of hydrochloric acid 0.5 N (30 mL) and water (3×30 mL). The organic layer was dried, filtered and concentrated to dryness. The crude thiocarbonylated intermediate was directly treated with tris-(trimethylsilyl)silane hydride (0.78 mL, 5.23 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.112 g, 0.69 mmol) in dry dioxane (17 mL) at reflux for 2 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane) to give pure 4 (0.93 g, 96%) as a foam: 1H NMR (DMSO-d6):δ 2.9-3.1 (m, 2H, H-2′ and H-2″), 4.6-4.7 (m, 3H, H-4′, H-5′ and H-5″), 5.8 (br s, 1H, H-3′), 6.43 (dd, 1H, H-1′, J1′, 2′,=3.1 Hz, J1′,2″=7.6 Hz), 7.3 (br s, 2H, NH2-6), 7.4-7.9 (m, 1H, 2 benzoyls), 8.05 and 8.33 (2s, 2H, H-2 and H-8); ms : matrix G/T, (FAB+) m/z 460 [M+H]+, 325 [S]+, 136 [BH2]+, (FAB-) m/z 458 [M-H]-, 134 [B]-; WV (95% ethanol):λmax261 nm (ε 14400), 231 nm (ε 26300), λmin249 nm (ε 12000); [α]D20 =38 (c 1.04, DMSO). After concentration the residue was dissolved in dichloromethane (50 mL) washed successively with water (2×30 mL), aqueous solution of hydrochloric acid 0.5 N (30 mL) and water (3×30 mL) The organic layer was dried filtered concentrated to dryness at reflux for 2 h The solvent was removed under vacuum the residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane)

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

Procedure: Pyridine (2.4 g, 31 mmol) was added to a stirred solution of 5-hydroxyethylisoxazole-3-carboxylic acid ethyl ester (4.75 g, 26 mmol) (prepared analogously to Example 64 part a) in dichloromethane (150 ml) under nitrogen at room temperature. The mixture was cooled to 0° C. and phenyl chlorothionoformate (5.3 g, 31 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hand at room temperature for 2 h, then diluted with dichloromethane (200 ml) and washed with water (×2). The organic layer was dried MgSO4) and evaporated in, vacuo. Flash chromatography of the residue on silica gel, eluting with 20% ethyl acetate/hexane, gave the title-compound (6.7 g, 81%), 1H NMR (250 MHz, CDCl3) δ 1.43 (3H, t, J=7.1 Hz, CH3), 3.37 (2H, t, J=6.3 Hz, CH2), 4.46 (2H, q, J=7.1 Hz, CH2), 4.83 (2H, t, J=6.3 Hz, CH2), 6.60 (1H, s, Ar—H), 7.08-7.11 (2H, m, 2 of Ar—H), 7.29 (1H, m, Ar—H), 7.38-7.46 (2H, m, 2 of Ar—H); MS (ES+) m/e 322 [MH]+, m/e 168 [MH—154]+. washed with water (×2) evaporated in, vacuo Flash chromatography of the residue on silica gel, eluting with 20% ethyl acetate/hexane

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

Procedure: To a solution of 3-[((3aR,7aR)-2,2-dimethyl-hexahydro-1,3-benzodioxol-3a-yl) hydroxymethyl]-1-(tertbutyldiphenyl-silyloxy)benzene (45 g) in CH2Cl2 (450 ml) were added phenyl chlorothionoformate (14.5 ml) and pyridine (18 ml) at 0° C. After being stirred for 12 hours at room temperature, the mixture was evaporated and the resultant was partitioned between EtOAc and water. The organic layer was washed with water, 1N-HCl solution, sat.NaHCO3 solution and then brine. The solvent was evaporated in vacuo to give an oily residue. The residue was dissolved in toluene (400 ml) to which tributyltinhydride (50 ml) and 2,2′-azobis-(isobutyronitrile)(100 mg) were added. The mixture was refluxed for 4 hours under stirring and then purified by chromatography on silica gel to give an oily compound. The oily compound was dissolved in a mixture of MeOH (200 ml) and THF (100 ml), to which p-toluenesulphonic acid (200mg) was added at room temperature. The mixture was stirred for 12 hours and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with water, sat. NaHCO3 solution and then brine. The solvent was evaporated in vacuo to give (1R,2R)-1-[3-(tertbutyldiphenylsilyloxy)benzyl]-1,2-dihydroxycyclohexane (30 g). the mixture was evaporated the resultant was partitioned between EtOAc and water The organic layer was washed with water, 1N-HCl solution The solvent was evaporated in vacuo to give an oily residue were added The mixture was refluxed for 4 hours under stirring purified by chromatography on silica gel to give an oily compound was added at room temperature The mixture was stirred for 12 hours evaporated The residue was partitioned between EtOAc and water The organic layer was washed with water, sat. NaHCO3 solution The solvent was evaporated in vacuo

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

Procedure: To 3,4-dimethyl-2-methoxyaniline(4.50 g, 0.03 mol), methylene chloride(100 ml) was added and then phenyl chlorothionoformate(5.16 g, 0.03 mol) was added slowly. The resulting mixture was stirred for 2 hours, and thereto water(150 ml) was added. The resulting mixture was extracted with methylene chloride and purified by column chromatography to obtain the titled compound. The resulting mixture was extracted with methylene chloride purified by column chromatography