2-(2-hydroxyethylsulfanyl)ethanol

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

Procedure: N,N,N′,N′-Tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 636 mg (1.745 mmol), and bis(2-hydroxyethyl)sulfide, 1 mL (9.67 mmol), were dissolved in 8 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 1.8 mL of 1 M solution in tetrahydrofuran (1.8 mmol), was added over a 10 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. It was then diluted with ethyl acetate; and the ethyl acetate layer separated, washed with 1 M hydrochloric acid and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate), and obtained as a colorless oil, 335 mg (42.6% yield), identified by HPLC and 1H and 31P NMR. to warm to room temperature and the ethyl acetate layer separated washed with 1 M hydrochloric acid and brine dried over anhydrous magnesium sulfate the ethyl acetate removed under vacuum The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate) obtained as a colorless oil, 335 mg (42.6% yield)

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

Procedure: To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 15.0 g, 65 mmol), 2,2′-thiodiethanol (40 g, 325 mmol) and N,N-dimethylaminopyridine (DMAP, 1.59 g, 13 mmol) in dichloromethane (400 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 14.98g, 78 mmol) as a solid, in portions. After stirring for 3 hours at room temperature, TLC analysis indicated the reaction was complete. The reaction mixture was partitioned between CH2Cl2 and water, and the water layer was washed with more CH2Cl2. The combined organic layer was washed with water, 0.1 N HCl, water, brine, and dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 5% ethyl acetate/dichloromethane. The appropriate fractions were combined, and the solvent evaporated. Trituration of the residue with ether/hexane gave the title compound as a white solid (17.72 g, 81% yield). Mp 58-61° C. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.6 Hz, 2H), 7.67 (d, J=0.9 Hz, 1H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.14 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 3.86 (q, J=7.2 Hz, 1H), 3.60 (app q, J=6.0 Hz, 2H), 2.69 (t, J=6.6 Hz, 2H), 2.61 (t, J=5.9 Hz, 2H), 2.00 (t, J=6.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 352 (MNH4+); Anal. calcd. for C18H22O4S: C, 64.65; H, 6.63; S, 9.59; Found: C, 64.62; H, 6.59; S, 9.47. The reaction mixture was partitioned between CH2Cl2 and water the water layer was washed with more CH2Cl2 The combined organic layer was washed with water, 0.1 N HCl, water, brine dried over magnesium sulfate The solution was concentrated under vacuum the residue was purified via column chromatography, 5% ethyl acetate/dichloromethane the solvent evaporated

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

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

Procedure: 0.2 mol of methyl 3-(3,5-dicyclohexyl-4-hydroxyphenyl)propionate, 0.1 mol of 1,5-dihydroxy-3-thiapentane and 2 ml of tetrabutyl titanate are heated for 8 hours at 150° C. as described in Example 2, during which time the methanol forming distills off. After working up, the yield of product is 25.5% of theory. distills off

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

Procedure: 0.2 mol of methyl 3-(3,5-dicyclohexyl-4-hydroxyphenyl)propionate, 0.1 mol of 1,5-dihydroxy-3-thiapentane and 2 ml of tetrabutyl titanate are heated for 8 hours at 150° C. as described in Example 2, during which time the methanol forming distills off. After working up, the yield of product is 25.5% of theory. distills off

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N,N′,N′-Tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 636 mg (1.745 mmol), and bis(2-hydroxyethyl)sulfide, 1 mL (9.67 mmol), were dissolved in 8 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 1.8 mL of 1 M solution in tetrahydrofuran (1.8 mmol), was added over a 10 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. It was then diluted with ethyl acetate; and the ethyl acetate layer separated, washed with 1 M hydrochloric acid and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate), and obtained as a colorless oil, 335 mg (42.6% yield), identified by HPLC and 1H and 31P NMR. to warm to room temperature and the ethyl acetate layer separated washed with 1 M hydrochloric acid and brine dried over anhydrous magnesium sulfate the ethyl acetate removed under vacuum The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate) obtained as a colorless oil, 335 mg (42.6% yield)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N,N′,N′-Tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 636 mg (1.745 mmol), and bis(2-hydroxyethyl)sulfide, 1 mL (9.67 mmol), were dissolved in 8 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 1.8 mL of 1 M solution in tetrahydrofuran (1.8 mmol), was added over a 10 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. It was then diluted with ethyl acetate; and the ethyl acetate layer separated, washed with 1 M hydrochloric acid and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate), and obtained as a colorless oil, 335 mg (42.6% yield), identified by HPLC and 1H and 31P NMR. to warm to room temperature and the ethyl acetate layer separated washed with 1 M hydrochloric acid and brine dried over anhydrous magnesium sulfate the ethyl acetate removed under vacuum The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate) obtained as a colorless oil, 335 mg (42.6% yield)

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

Procedure: In dichloromethane (200 ml) were dissolved 2,2′-thiodiethanol (10.0 g, 81.8 mmol) and imidazole (4.70 g, 69.0 mmol), followed by the dropwise addition of t-butylchlorodiphenylsilane (15.0 ml, 57.7 mmol) at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. After concentration under reduced pressure, diethyl ether was added to the residue. Then, the insoluble matter was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure, whereby the title compound (11.3 g, 31.3 mmol, 54%) was obtained as a colorless oil. After completion of the dropwise addition After concentration under reduced pressure, diethyl ether was added to the residue Then, the insoluble matter was filtered off The residue obtained by concentrating the filtrate under reduced pressure the fraction obtained from the hexane