methyl (2S,3S,4S,5R,6R)-3,4,5-triacetyloxy-6-bromooxane-2-carboxylate

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

Procedure: Following a procedure similar to that of Example 1 but using 1.442 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 4.37 g of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranuronate there was obtained methyl 1-O-[5-carbamoyl-1-(4-nitrobenzyl)imidazole-4-yl]-2,3,4-tri-O-acetyl-β-D-glucopyranuronate. The resulting product as such was used as the starting compound in the following Example 19.

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2.33 g (10 mmol) (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, 3.58 g (9 mmol) acetobromo-α-D-glucuronic acid methyl ester and 0.23 g (9.5 mmol) lithium hydroxide in 23 ml dry methanol was first stirred at 20° C. for 30 minutes, a solution of 0.65 g lithium hydroxide in 25 ml water was then added and the mixture was stirred again for 30 minutes. It was extracted with ethyl acetate and the aqueous phase was adjusted to a pH of 3.5 by addition of acetic acid and extracted again with ethyl acetate. The aqueous phase was evaporated in vacuo and the residue was purified by HPLC. 0.85 g (23% of theory) of the title compound was obtained in this manner in the form of a white powder. the mixture was stirred again for 30 minutes It was extracted with ethyl acetate the aqueous phase was adjusted to a pH of 3.5 by addition of acetic acid extracted again with ethyl acetate The aqueous phase was evaporated in vacuo the residue was purified by HPLC

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

Procedure: Following a procedure similar to that of Example 1 but using 1.442 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 4.37 g of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranuronate there was obtained methyl 1-O-[5-carbamoyl-1-(4-nitrobenzyl)imidazole-4-yl]-2,3,4-tri-O-acetyl-β-D-glucopyranuronate. The resulting product as such was used as the starting compound in the following Example 19.

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

Procedure: Following a procedure similar to that of Example 1 but using 1.442 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 4.37 g of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranuronate there was obtained methyl 1-O-[5-carbamoyl-1-(4-nitrobenzyl)imidazole-4-yl]-2,3,4-tri-O-acetyl-β-D-glucopyranuronate. The resulting product as such was used as the starting compound in the following Example 19.

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

Procedure: A solution of tanaproget (0.292 g, 1.0 mmol) in anhydrous dimethyl formamide (DMF) (10 mL) was added dropwise under a nitrogen atmosphere to a solution of sodium hydride (NaH) (0.052 g, 2.2 mmol) in DMF (50 mL) that was cooled to approximately −70° C. (dry ice). After stirring for 10 min, a solution of acetobromo-α-D-Glucuronic acid methyl ester (0.396 g, 1 mmol) in DMF (10 mL) was added dropwise. The reaction solution was then warmed to room temperature, and stirred for a total of 24 hours. After 24 hours, the reaction solution was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The combined organic layers were washed with saturated sodium chloride (NaCl) solution (100 mL), dried (magnesium sulfate, MgSO4), and the solvent removed in vacuo. Aliquots of the crude material were chromatographed under low-pressure reversed-phase C18 (RediSep/ISCO, 125×25 mm ID, 40 μm particle size) conditions with a gradient of 50-95% acetonitrile/water. Fractions eluting with 75-80% acetonitrile/water contained the S-protected (D)-Glucuronic acid derivative (2) of tanaproget. A total of approximately 200 mg of (2) was obtained at 95% purity based on NMR spectroscopic analysis (32% isolated yield). All chemicals were purchased from Aldrich (Milwaukee, Wis.) and used without further purification or drying. stirred for a total of 24 hours After 24 hours the reaction solution was partitioned between water (100 mL) and ethyl acetate (100 mL) The aqueous layer was extracted again with ethyl acetate (100 mL) The combined organic layers were washed with saturated sodium chloride (NaCl) solution (100 mL) dried (magnesium sulfate, MgSO4) the solvent removed in vacuo Aliquots of the crude material were chromatographed under low-pressure reversed-phase C18 (RediSep/ISCO, 125×25 mm ID, 40 μm particle size) conditions with a gradient of 50-95% acetonitrile/water Fractions eluting with 75-80% acetonitrile/water

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

Procedure: A solution of tanaproget (0.292 g, 1.0 mmol) in anhydrous dimethyl formamide (DMF) (10 mL) was added dropwise under a nitrogen atmosphere to a solution of sodium hydride (NaH) (0.052 g, 2.2 mmol) in DMF (50 mL) that was cooled to approximately −70° C. (dry ice). After stirring for 10 min, a solution of acetobromo-α-D-Glucuronic acid methyl ester (0.396 g, 1 mmol) in DMF (10 mL) was added dropwise. The reaction solution was then warmed to room temperature, and stirred for a total of 24 hours. After 24 hours, the reaction solution was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The combined organic layers were washed with saturated sodium chloride (NaCl) solution (100 mL), dried (magnesium sulfate, MgSO4), and the solvent removed in vacuo. Aliquots of the crude material were chromatographed under low-pressure reversed-phase C18 (RediSep/ISCO, 125×25 mm ID, 40 μm particle size) conditions with a gradient of 50-95% acetonitrile/water. Fractions eluting with 75-80% acetonitrile/water contained the S-protected (D)-Glucuronic acid derivative (2) of tanaproget. A total of approximately 200 mg of (2) was obtained at 95% purity based on NMR spectroscopic analysis (32% isolated yield). All chemicals were purchased from Aldrich (Milwaukee, Wis.) and used without further purification or drying. stirred for a total of 24 hours After 24 hours the reaction solution was partitioned between water (100 mL) and ethyl acetate (100 mL) The aqueous layer was extracted again with ethyl acetate (100 mL) The combined organic layers were washed with saturated sodium chloride (NaCl) solution (100 mL) dried (magnesium sulfate, MgSO4) the solvent removed in vacuo Aliquots of the crude material were chromatographed under low-pressure reversed-phase C18 (RediSep/ISCO, 125×25 mm ID, 40 μm particle size) conditions with a gradient of 50-95% acetonitrile/water Fractions eluting with 75-80% acetonitrile/water

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

Procedure: To a solution of the compound of Example 14 (0.997 g, 2.05 mmol) in acetonitrile (20 mL) is added potassium carbonate (0.284 g, 2.05 mmol) and the reaction mixture stirred for 0.5 hr. (2R,3R,4S,5S,6S)-2-Bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.817 g, 2.05 mmol) is added to the reaction mixture and the reaction stirred for 12 hr. The reaction mixture is filtered and the filtrate concentrated under reduced pressure on a rotary evaporator to give a crude product. The crude product is purified by column chromatography on silica gel eluted with ethyl acetate-hexane (2:8) to yield the title compound (1.0 g, 60%). MS m/z 801.1 (M+.+1); 1H NMR (CDCl3, 200 MHz) δ 5.65 (C-6 pyran H, d, J5,6=8 Hz). the reaction stirred for 12 hr The reaction mixture is filtered the filtrate concentrated under reduced pressure on a rotary evaporator to give a crude product The crude product is purified by column chromatography on silica gel eluted with ethyl acetate-hexane (2:8)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2.33 g (10 mmol) (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, 3.58 g (9 mmol) acetobromo-α-D-glucuronic acid methyl ester and 0.23 g (9.5 mmol) lithium hydroxide in 23 ml dry methanol was first stirred at 20° C. for 30 minutes, a solution of 0.65 g lithium hydroxide in 25 ml water was then added and the mixture was stirred again for 30 minutes. It was extracted with ethyl acetate and the aqueous phase was adjusted to a pH of 3.5 by addition of acetic acid and extracted again with ethyl acetate. The aqueous phase was evaporated in vacuo and the residue was purified by HPLC. 0.85 g (23% of theory) of the title compound was obtained in this manner in the form of a white powder. the mixture was stirred again for 30 minutes It was extracted with ethyl acetate the aqueous phase was adjusted to a pH of 3.5 by addition of acetic acid extracted again with ethyl acetate The aqueous phase was evaporated in vacuo the residue was purified by HPLC

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

Procedure: Following a procedure similar to that of Example 1 but using 1.442 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 4.37 g of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranuronate there was obtained methyl 1-O-[5-carbamoyl-1-(4-nitrobenzyl)imidazole-4-yl]-2,3,4-tri-O-acetyl-β-D-glucopyranuronate. The resulting product as such was used as the starting compound in the following Example 19.