(2R,4S)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate

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

Procedure: To a mixture of Example 17A (19.9 g, 66 mmol) and triethylamine (9.5 mL, 70 mmol) in THF (200 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (15.08 g, 132 mmol) drop wise over 30 minutes. The mixture was allowed to warm up to room temperature, stirred for 12 hours, and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to a yellow oil. The yellow oil was purified using a Biotage 65+ eluting with 100% ethyl acetate to provide the titled compound. MS (ESI) m/e 380 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.44 (m, 9 H) 2.22 (m, 1 H) 2.65 (m, 1 H) 3.05 (m, 1 H) 3.14 (d, 3 H) 3.17 (m, 1 H) 3.74 (m, 3.73 Hz, 1 H) 3.81 (m, 2 H) 4.00 (m, 1 H) 4.53 (m, 1 H) 4.70 (m, 2 H) 5.32 (m, 1 H). concentrated under reduced pressure The residue was partitioned between water and ethyl acetate the aqueous layer was extracted with ethyl acetate (3×300 mL) The combined organic layers were dried (magnesium sulfate) filtered concentrated to a yellow oil The yellow oil was purified 65+ eluting with 100% ethyl acetate

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

Procedure: (2S, 4R)-4-Hydroxy-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.34 g, 0.0111 mol, Example 17A) was dissolved in DMSO and cooled to 0° C. To the cold solution, triethylamine (7.37 g, 0.0729 mol) and sulfur trioxide pyridine complex (8.44 g, 0.0530 mol) were added. The mixture was stirred at 0° C. for 2 hours, brought to room temperature and quenched with water. The mixture was extracted with ethyl acetate and washed with 1 M HCl (60 mL), saturated NaHCO3 (2×40 mL) and brine (1×30 mL). The organic layer was dried with Na2SO4, filtered, concentrated, and purified by column chromatography (ethyl acetate/hexane, 1/1) to give the titled compound 2.05 g. MS (ESI APCI) m/e 299 (M−H)+; 1H NMR (300 MHz, methanol-d4): δ ppm 5.07 (d, 1 H), 4.80 (m, 1 H), 4.57-4.68 (m, 2 H), 4.45 (m, 1 H), 3.85 (d, 2 H), 3.78 (m, 2 H), 3.17 (t, 1 H), 3.05 (m, 2 H), 2.44-2.49 (d, 1 H), 1.47 (s, 9 H). brought to room temperature quenched with water The mixture was extracted with ethyl acetate washed with 1 M HCl (60 mL), saturated NaHCO3 (2×40 mL) and brine (1×30 mL) The organic layer was dried with Na2SO4 filtered concentrated purified by column chromatography (ethyl acetate/hexane, 1/1)

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

Procedure: 3-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (title compound of Reference Example 9, 56.3 g) and triethylamine (28.5 mL) were dissolved in dichloromethane (1.0 l), and methanesulfonyl chloride (15.1 mL) was added thereto under ice-cooling. After stirring under ice-cooling for 1 hr, the reaction mixture was washed with water and dried. The solvent was evaporated under reduced pressure to give 3-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (70.5 g) as an oil.

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

Procedure: 3-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (title compound of Reference Example 9, 56.3 g) and triethylamine (28.5 mL) were dissolved in dichloromethane (1.0 l), and methanesulfonyl chloride (15.1 mL) was added thereto under ice-cooling. After stirring under ice-cooling for 1 hr, the reaction mixture was washed with water and dried. The solvent was evaporated under reduced pressure to give 3-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (70.5 g) as. an oil.

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

Procedure: To a mixture of Example 17A (19.9 g, 66 mmol) and triethylamine (9.5 mL, 70 mmol) in THF (200 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (15.08 g, 132 mmol) drop wise over 30 minutes. The mixture was allowed to warm up to room temperature, stirred for 12 hours, and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to a yellow oil. The yellow oil was purified using a Biotage 65+ eluting with 100% ethyl acetate to provide the titled compound. MS (ESI) m/e 380 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.44 (m, 9H) 2.22 (m, 1H) 2.65 (m, 1H) 3.05 (m, 1H) 3.14 (d, 3H) 3.17 (m, 1H) 3.74 (m, 3.73 Hz, 1H) 3.81 (m, 2H) 4.00 (m, 1H) 4.53 (m, 1H) 4.70 (m, 2H) 5.32 (m, 1H). concentrated under reduced pressure The residue was partitioned between water and ethyl acetate the aqueous layer was extracted with ethyl acetate (3×300 mL) The combined organic layers were dried (magnesium sulfate) filtered concentrated to a yellow oil The yellow oil was purified 65+ eluting with 100% ethyl acetate

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

Procedure: (2S, 4R)-4-Hydroxy-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.34 g, 0.0111 mol, Example 17A) was dissolved in DMSO and cooled to 0° C. To the cold solution, triethylamine (7.37 g, 0.0729 mol) and sulfur trioxide pyridine complex (8.44 g, 0.0530 mol) were added. The mixture was stirred at 0° C. for 2 hours, brought to room temperature and quenched with water. The mixture was extracted with ethyl acetate and washed with 1 M HCl (60 mL), saturated NaHCO3 (2×40 mL) and brine (1×30 mL). The organic layer was dried with Na2SO4, filtered, concentrated, and purified by column chromatography (ethyl acetate/hexane, 1/1) to give the titled compound 2.05 g. MS (ESI APCI) m/e 299 (M−H)+; 1H NMR (300 MHz, methanol-d4): δ ppm 5.07 (d, 1H), 4.80 (m, 1H), 4.57-4.68 (m, 2H), 4.45 (m, 1H), 3.85 (d, 2H), 3.78 (m, 2H), 3.17 (t, 1H), 3.05 (m, 2H), 2.44-2.49 (d, 1H), 1.47 (s, 9H). brought to room temperature quenched with water The mixture was extracted with ethyl acetate washed with 1 M HCl (60 mL), saturated NaHCO3 (2×40 mL) and brine (1×30 mL) The organic layer was dried with Na2SO4 filtered concentrated purified by column chromatography (ethyl acetate/hexane, 1/1)