tert-Butyl 3-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate

To a stirred solution of fert-butyl 3-hydroxypyrrolidine-l-carboxylate (16 g, 85.4 mmol) and triethylamine (19 mL, 129 mmol) in 130 mL CHTo a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.34 mmol) in DCM (17 mL) was added TEA (0.962 mL, 6.94 mmol) followed by MsCl (0.499 mL, 6.41 mmol) at 0° C. tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (515 mg, 2.75 mmol) was dissolved in methylene chloride (4.2 mL) and stirred at 0 ° C. Methanesulfonyl chloride (234 μL, 3.00 mmol) and triethylamine (0.42 mL, 3.00 mmol) were added and the mixture was stirred at room temperature for 30 minutes under argon. After the reaction was completed, the organic solvent layer extracted with water and ethyl acetate was dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain tert-butyl 3 - ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 737 mg, 2.78 mmol) in a yield of 100percent.Methanesulfonyl chloride (1.12 g, 10 mmol) was added dropwise to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate(1.87 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in 20 ml of dichloromethane and reacted at room temperature for 1 hour. The reaction was quenched by adding cold saturated aqueous sodium bicarbonate to the system. The organic phase was separated, washed with water, dried and concentrated to give the title compound (2.65 g, 100percent).Triethylamine (35 g, 346 mmol, 2.1 eq.) and methanesulfonyl chloride (36.6 g, 321 mmol, 1.9 eq.) were added subsequently to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (30.0 g, 163 mmol, 1.0 eq.) in dichloromethane (200 mL) at 0° C. EtThe compound tert-butyl 3-hydroxypyrrolidine-1-carboxylate 7a (561 mg, 3.0 mmol), methylsulfonyl chloride(410 mg, 3.6 mmol), triethylamine (606 mg, 6.0 mmol) and dichloromethane (50 mL) were added and stirred at room temperature for 4 hours.The mixture was diluted with 50 mL of methylene chloride and washed successively with saturated ammonium chloride solution (20 mL) and saturated brine (20 mL x 2)Polyester. The organic phase was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration and depressurized under reduced pressure to give the desired productTert-butyl 3 - ((methylsulfonyl) oxo) pyrrolidine-1-carboxylate 7b (790 mg) in 99percent yield. The product was used directly in the next step without purificationTo a stirred solution of tert-butyl 3-hydroxypyrrolidine-1 -carboxylate(mixture of isomers, 5.1 g, 27.2 mmol) in DCM (75 mL), TEA (5.9 mL, 42.7 mmol) was added at room temperature. The mixture was cooled to000 then methane sulfonyl chloride (2.62 mL, 32.7 mmol) was addeddropwise. The resulting solution was stirred at room temperature for 1 hthen was diluted with DCM (100 mL) and washed with water (50 mL)and brine (50 mL). The organic layer was dried over sodium sulfate andconcentrated to afford the title compound (7.15 g, 99percent yield) as a mixture of isomers, that was progressed without any further purification.1HNMR (CDCI3): 6 5.30-5.27 (m, 1H), 3.60-3.58 (m, 4H), 3.05 (5, 3H), 2.19-2.16 (m, 1H), 2.13-2.12 (m, 1H), 1.39 (5, 9H).To a solution of compound 45-1 (10 g, 53.5 mmol) and TEA (6.5 g, 64.2 mmol) in DCM (100 mL) was added dropwise mesyl chloride (7.35 g, 64.2 mmol), and the reaction solution was reacted at r.t. for 1 h. To this solution, water (80 mL) was added and the resulting solution was extracted with DCM (100 mL×2). The organic phases were combined, dried over anhydrous NaPreparation Example 1-55-13-Methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester 3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.94 g, 5.0 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C., and then diisopropylethylamine (0.97 g, 7.5 mmol) and methanesulfonylchloride (0.63 g, 5.5 mmol) were added thereto. The mixture was stirred at room temperature for 16 hours, distilled under reduced pressure to remove the solvent, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure, and purified by column chromatography using 2:1 mixture solvent of hexane and ethyl acetate to obtain the title compound (1.27 g, 95percent).Step A: 3-Methanesulfonyloxy-pyrrolidme-l-carboxyric acid tert-butγl esterTo a solution of the fert-butyl 3 -hydroxy- 1 -pyrrolidinecarboxylate (5.00 g, 26.7 mmol) in dichloromethane (50 mL) is added pyridine (10 mL, 122.6 mmol) and DMAP (0.56 g, 4.6 mmol). The mixture is then cooled to 0 Step 1: tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate; To a solution of tert-butyl 3-hydroxypyrrolidine-i-carboxylate (Aldrich; 7.42 g, 39.6 mmol), in DCM (20 ml.) was added, at 0 To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.34 mmol, 1.0 eq) in DCM (10 ml) were added TEA (1.08 g, 10.68 mmol, 2.0 eq) and DMAP (65 mg, 0.53 mmol). N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 μl) were added thereto at 0°C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z[M+H]N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 μl) were added thereto at 0° C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z[M+H]N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 μl) were added thereto at 0° C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z [M+H]The compound, tert-butyl 3-hydroxypyrrolidine-1-carboxylate (4.00 g, 21.36 mmol)Dissolved in DCM (50 mL)Cooled to 0 ° C and then Et3N (4.7 mL, 32.04 mmol) was added slowly to the reaction followed by addition of MsCl (2.0 mL, 25.64 mmol) and DMAP (26.1 mg, 0.214 mmol) in DCM ) Solution, Warmed to room temperature, stirred for 4 hours, The reaction was quenched by the addition of water (50 mL) and the resulting mixture was extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound as a yellow oil (6.63 g, 117.0percent).ter^-Butyl 3-[(methyIsulfonyl)oxy]pyrrolidine-l-carboxylate; 5 tert-Butyl 3-hydroxypyrrolidine-l-carboxylate (3.0Og, 16.02mmol) was dissolved in dry DCM (5OmL) and cooled in an ice-water bath. Methanesulfonyl chloride (2.38g, 20.83mmol) was added followed by TEA (2.43g, 24.03mmol) and the reaction mixture was stirred at 0°C for 3.5h. The reaction mixture was washed with water (25OmL) and dried with MgSOTo a stirred solution of 6-bromo-3-butyl-1H-pyrrolo[3, 2-c]pyridine (500 mg, 01.975mmol) in DMF (50 mL) was added CS2CO3 (2.24g, 6.9mmol) at RT. Resulting reaction mixture was allowed to stir at 100C for 1 h, then was added tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1 -carboxylate in DMF (1.04g, 3.95mmol), then heated for 2 h. The reaction was monitored by LCMS. The reaction mixture was cooled, 20 mi ice cold water was added and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate. The crude was purified by flash column chromatography in devisal silica using 25-30% EtOAc/pet ether to get tert-butyl 3-(6- bromo-3-butyl-1 H-pyrrolo[3, 2-c]pyridin-1 -yl)pyrrolidine-1 -carboxyiate (0.39 g, 46.8 %) as pale yellow gum. LC-MS (method 23): Rt = 2.43 min; m/z = 423.55 (M+H+).3-Methanesulfonyloxy-pyrrolidine- 1 -carboxylic acid tert-butyl ester (CAS 141699-57-2, 768 mg, 2.89 mmol, 1.00 equiv) was dissolved in Et20 (8.7 mL) and HC1 (4 M in dioxane, 8.68 mL, 17.4 mmol, 6 equiv) was added. The mixture was stuffed overnight, concentrated and the residue was used without further purification.

Molecular Weight:265.33
XLogP3:0.7
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:265.09839388
Monoisotopic Mass:265.09839388
Topological Polar Surface Area:81.3
Heavy Atom Count:17
Complexity:379
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes