4-[(Methylsulfonyl)oxy]piperidine-1-carboxylic acid tert-butyl ester

White powder

Synthesis of NTo a solution of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (4.0 g, 20.0 mmol) and triethylamine (4.0 g, 40 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (2.8 g, 24.4 mmol) at 0 To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (4.O g, 20.0 mmol) and triethylamine (4.0 g, 40 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (2.8 g, 24.4 mmol) at 0 tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylateStep A: tert-butyl 4-[(methylsulfonv0oxylpiperidine-1-carboxylateA solution of ferf-butyl 4-hydroxypiperidine-1-carboxylate (32.2 g, 0.160 mol) in DCM (400 mL) cooled to 0 °C, was treated with triethylamine (26.8 mL, 0.192 mol), methanesulfonyl chloride (13.6 mL, 0.176 mol), and 4-dimethylaminopyridine (0.20 g, 0.0016 mol) at 0 °C under nitrogen atmosphere. The resulting mixture was slowly warmed to RT and stirred overnight. The mixture was washed with saturated aqueous NaHC0To a solution of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (4.0 g, 20.0 mmol) and triethylamine (4.0 g, 40 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (2.8 g, 24.4 mmol) at 0 °C. The solution was stirred at 0 °C for 10 min, then at room temperature for 2 h. The reaction mixture was partitioned between 10percent citric acid and ethyl acetate. The organic layer was washed with sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to give 1/2rt-butyl 4- (methylsulfonyloxy)piperidine-l -carboxylate (6.4 g, quantitative yield). MS (EI) for C, iH5) N-tert-butyloxycarbonyl-4-piperidinol (50.0 g, 249 mmol) was dissolved in dry dichloromethane (300 mL). To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (7.94 g, 39.45 mmol) in DCM (100 mL) was added EtA mixture of N-Boc-4-hydroxypiperidine (2200 g, 10.95 mol) in anhydrous DCM (8 L) was added triethylamine (2284 mL, 16.42 mol) in one portion at 0°C, then MsC1 (1316 g 11.49 mol) was added drop wise into the mixture at 0°C, then the mixture was allowed to stir at room temperature for 2 hours. TLC (petroleum ether: EtOAc = 1:1, Rf = 0.6) showed the reaction was complete. Water (2 L) was added into the mixture and the organic phase was separated, and then the organic phase was washed with 1 M hydrochloride solution (4 L), saturated NaHCO3 solution (4 L), brine (1L), and dried over anhydrous Na2SO4, then the mixture was concentrated in vacuo to provide compound mt 4-5 (3120 g, 100 percent) which was used for the next step without further purification.To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.01 g, 5.02 mmol) in DCM (16 mL) was added TEA (0.909 mL, 6.52 mmol) and DMAP (61.0 mg, 0.502 mmol) followed by MsCl (0.469 mL, 6.02 mmol) at 0° C. The N-tert-butoxycarbonyl-4-piperidinol (5.0g, 25mmol) and triethylamine (5.06g, 50mmol) dissolved in anhydrous dichloromethane (30 ml) in, the reaction system is cooled to 4 degree c, adding MsCl (3.45g, 30mmol). Is omitted, to eliminate ice-bath, the reaction room temperature for 2 hours. Achieve the terminal point a reaction TLC, for rotary evaporimeter jeung dry dichloromethane, water residues 30 ml, extraction with ethyl acetate (30mLx3). Combined with the phase, water (100mLx1) and saturated ammonium chloride aqueous solution (100mLx1) washing, drying by anhydrous sodium sulfate 1 hour. Filtering, filtering the drying agent, the filtrate to dryness under reduced pressure using rotary evaporimeter, to obtain compound 1 (6.9g, quantitative yield), the solid powder of white.At 0 °C, a solution of te/f-butyl 4-hydroxypiperidine-1-carboxylate, intermediate 8 (10 g, 50 mmol) and TEA (10 g, 100 mmol) in anhydrous DCM (100 mL) was treated with MsCI (6.9 g, 59 mmol). After stirring at room temperature for 2 hr, the resulting mixture was quenched with sat. NHIce bath, Methylsulfonyl chloride (2.44 g, 21.3 mmol, 1.65 mL)Slow dropwise addition of tert-butyl-N-formate-4-hydroxypiperidine (3.10 g, 15.00 mmol) andTriethylamine (3.00 g, 30 mmol, 4.00 mL)In dichloromethane (40 mL), After completion of the dropwise addition, the reaction was carried out at room temperature for 1.5 h.The reaction was quenched with hydrochloric acid (1 M, 40 mL) for the addition of the reaction solution. The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, To give 4.30 g of an off-white solid in a yield of 100.0percent.he compoundTert-butyl 4-hydroxytyridine-1-carboxylate(7.94 g, 39.45 mmol)Dissolved in DCM (100 mL), coldBut to 0 ° C, then to the reaction mixture was slowly added Et3N (8.6mL, 59.18mmol), MsCl (3.7 mL, 47.34 mmol)And DMAP (48.0 mg, 0.390 mmol) in DCM (3 mL) and the reaction stirred at room temperature for 1 hour.The reaction was quenched by adding water (30 mL) and the mixture was extracted with DCM (30 mL x 3).The combined organic phases were washed with brine (80 mL × 3), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the title compound as a white solid (11.11 g, 100percent).Step 3. The tert-butyl4-(methylsulfonyloxy)piperidine-l -carboxylate used in this step was made as follows:To tert-butyl 4-hydroxypiperidine-l -carboxylate (leq) in methylene chloride and triethyl amine (1.4eq) at 0°C was added methane sulfonyl chloride ( 1.4 eq) drop- wise. The reaction was brought to ambient temperature and was stirred for Ih. The reaction mixture was washed with water and saturated sodium chloride solution. The organic layer was then dried with sodium sulfate and concentrated to yield tert-butyl4-(methylsulfonyloxy)piperidine-l -carboxylate in quantitative yield. The product was confirmed by b) 4- (2-chloro-5-fluoro-phenoxy) -piperidine (8b) 9g (44.7mmol) of BOC-4-hydroxy-piperidine are placed in 3OmL of dichloromethane at 0To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (7.94 g, 39.45 mmol) in CHGeneral Procedure 65 To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid fert-butyl ester (7.94 g, 39.45 mmol) in CH4-methanesulfonyloxy-eridine-1-carboxylic acid tert-butyl ester (2)To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (7.94 g, 39.45 mmol) in CH2CI2 (100 mL), cooled to 0°C, was slowly added NEt3 (5.54 mL, 39.45 mmol) followed by methane sulfonyl chloride (3.06 mL, 39.45 mmol) and DMAP (48 mg, 0.39 mmol). The mixture was stirred at room temperature overnight. To the mixture was added water (30 mL). Extraction with CH2CI2 (3 x 30 mL) followed by drying (Na2504) and removal of the solvent in vacuo afforded 4-methanesulfonyloxy- piperidine-1-carboxylic acid tert-butyl ester as a white solid (11.00 g, >99percent yield). 1H NMR (CDCI3, 400 MHz) 4.89 (m, 1 H), 3.69 (m, 2H), 3.31 (m, 2H), 3.04 (s, 3H), 1.95 (m, 2H), 1.83 (m, 2H), 1.46 (s, 9H).To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (7.94 g, 39.45 mmol) in CHtert-Butyl 4-hydroxypiperidine-1-carboxylate 10 (39.0 g, 193 mmol) was taken in DCM (400 mL) in a 1L round bottom flask under N2 and cooled it to 0°C To it were sequentially added methanesulfonyl chloride (28.7 g, 250.0 mmol) and Et3N (81 mL, 581.0 mmol). The reaction mixture was stirred at rt for 4h. The reaction mixture was then poured into ice water and extracted with DCM (3 x 100 mL). The combined organic layer was washed with saturated NaHCO3 solution (3 x 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was further washed with npentane to afford 11 as an off-white solid (54.0 g, 99percent yield). ‘H NMR (400 MHz, CDC13): 8 4.85-4.88 (m, 1H), 3.67-3.70 (m, 2H), 3.25-3.32 (m, 2H), 3.02 (s, 3H), 1.93- 1.94 (m, 2H), 1.76-1.84 (m, 2H), 1.44 (s, 9H).Step 1. tert-butyl 4-(methylsulfonyloxy)piperidine-l-carboxylate [0257] Methanesulfonyl chloride (2.90 mL, 37.6 mmol) was added to a 0 °C solution of tert-butyl 4- hydroxypiperidine- 1 -carboxylate (5.00 g, 24.8 mmol) and triethyl amine (10.4 mL, 74.65 mmol) in dichloromethane (50 mL), and the resulting solution stirred for 1 h at room temperature. The reaction mixture was diluted with dichloromethane (200 mL), washed with water (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 4- (methylsulfonyloxy)piperidine-l -carboxylate (7.00 g, 99percent) as a yellow solid. MS (ESI, pos. ion) m/z 280 [M+H]To a stirred solution of 1-boc-4-hydroxy piperidine (6.0 g, 29.8 mmol) in dry DCM (100 mL), TEA (8.48 g, 89.5 mmol) and mesyl chloride (5.12 g, 44.78 mmol) were added slowly at 0 °C. The reaction mixture was stirred at rt for 1 h. It was concentrated under vacuum and the resulting crude product was dissolved in DCM. The resulting solution was washed with brine, water, dried over anhydrous Na4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2) i) Intermediate 13-Synthesis of 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester As shown in step 3-i of Scheme 3, N-Boc-4-hydroxypiperidine (30 g, 149.1 mmol, 1 eq.), triethylamine (22.87 mL, 164 mmol, 1.1 eq.) and N, N-dimethylpyridin-4-amine (DMAP) (1.83 g, 14.98 mmol, 0.1 eq.) were dissolved in anhydrous methylene chloride (500 mL) and cooled to 0° C in an ice bath. Methanesulfonyl chloride (12.12 mL, 156.6 mmol, 1.05 eq.) was added dropwise. Upon completion of the addition, the reaction was warmed to room temperature and stirred for 16 hours. The reaction was washed with water (3 x 100 mL) and saturated sodium bicarbonate (3 x 100 mL). The combined aqueous washes were back-extracted with methylene chloride. The combined organics were dried over Natert-Butyl 4- hydroxypiperidine-1-carboxylate (60.0 g, 0.3 mol, 1.0 eq), methanesulfonyl chloride (37.6 g, 0.33 mol, 1.1 eq), and triethylamine (36.2 g, 0.36 mol, 1.2 eq) in 600 ml of dichloromethane (DCM) was stirred at room temperature overnight. Water (300 ml) was added and the layers were separated. The aqueous layer was extracted with DCM once. The combined organics were washed with brine, dried, and evaporated to a yellowish solid, 80.5 g, in 97percent yield.To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (50.0 g, 248 mmol) in CHDi-tert-butyl dicarbonate anhydride (12.83 mmol) was added in portions to a solution of triethylamine (1.30 g, 1.80 ml, 12.83 mmol) and 4-hydroxypiperidine 15 (9.88 mmol) in DCM (15 ml) at 0 °C. After completion of addition, the reaction mixture was warmed to room temperature (25 °C) and stirred for one hour. After completion of reaction (TLC), quenched with water and extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure to obtain 16 as white solid which was used in next step without further purification. Methanesulfonyl chloride (0.85 g, 0.58 ml, 7.44 mmol) was added drop-wise to a solution of tert-Butyl 4-hydroxylpiperidine-1-carboxylate 16 (1.25 g, 6.21 mmol) and triethylamine (0.75 g, 1.10 ml, 7.41 mmol) in DCM (12 mL) at 0 °C. After completion of addition, the reaction mixture was stirred at room temperature (25 °C) for 1 hour. After completion of reaction (TLC), the reaction was quenched with water and extracted with DCM. The combined DCM layer was washed with brine, dried over sodium sulphate and concentrated in vacuo to afford 17 (1.34 g, 97percent) as light yellow solid. 1H-NMR (400 MHz, CD3OD): δ 4.80 (m, 1H), 3.62-3.23 (m, 4H), 2.96 (s, 3H), 1.88-1.39 (m, 4H), 1.39 (s, 9H).Step B [1830] The title compound from Step A above (3.5 g, 17.39 mmoles) and triethylamine (4.85 mL, 34.79 mmoles) were dissolved in CH[2387] The title compound from Step A above (3.5 g, 17.39 mmoles) and triethylamine (4.85 mL, 34.79 mmoles) were dissolved in CH2Cl2 (30 mL) and the mixture was stirred under nitrogen at 0° C. Methanesulfonylchloride (1.62 mL, 20.88 mmoles) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (4.68 g, 96.4percent). ESMS: m/z=280 (MH+)Step 1: Step 1: To a solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (25.0 g, 124 mmol) and triethylamine (18.86 g, 186 mmol) in dichloromethane (250 mL) at 0 °C, was added methanesulfonylchloride (15.6 g, 136mmol) dropwise. After complete addition, reaction mixture warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the mesylatedcompound (33.0 g, 96.2percent) as a brown solid. PREPARATION 19 PREPARATION OF TERT-EUTYL 4-(4-(4, 4, 5, 5-TETRAMETHYL-1, 3, 2-DIOXABOROLAN-2-YL)- 1H-PYRA 1 -CARBOXYLATE A. To a cold solution (0 °C) of tert-butyl 4-hydroxypiperidine- 1- carboxylate (175 g, 0.87 mol) in 750 mL of dichloromethane was added triethylamine (237 mL, 1.74 mol) dropwise, followed by the addition of mesyl chloride (101 mL, 1.31 mol) dropwise. The resulting mixture was stirred at room temperature for 2 hours, then diluted with 400 mL of dichloromethane and washed with saturated sodium bicarbonate (2 x 750 mL), water (1 x 600 mL) and brine (1 x 600 mL). The organic solution was dried over anhydrous sodium sulfate, and filtered. Removal of the solvent afforded tert- butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate as a yellow solid in 96.8percent yield (235 g). 1H NMR (400 MHz, CDC1Vote T-260g, by adding dichloromethane solvent cleaning, then adding triethylamine, the 0 °C the following, dropping MeSO2Cl, TLC monitoring raw material the reaction is complete. The post-processed to obtain about 80g, yield 96percent.T-260g raw material, by adding 300 ml of the dichloromethane solvent cleaning, then adding 1.5 mole-equivalents of triethylamine (TEA), the 0 °C the following, dropping 1.5 mole equivalent of a sulfonyl chloride (eq). The post-processed to obtain about 80g, yield 96percent.Example 7A; 2-f4-f(3, 4-dichlorophenvπsuIfonyl|ρiperidin-l-yl>-3-('trifluoromethyl')pyridine; Step 7A. tert-butyl 4-[(methylsulfonyl)oxy]piperidine-l-carboxylate; The mesylate was prepared from tert-butyl-4-hydroxy-l-piperidinecarboxylate using the procedure from WO 0053362 Cheng S., et al. To a 0To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g) and tetrahydrofuran (100 mL) were successively added methanesulfonyl chloride (5.98 g) and triethylamine (5.53 g) at 0°C. The mixture was stirred at room temperature for 2 hrs., and the reaction mixture was diluted with ethyl acetate and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate as crystals. Recrystallization from ethyl acetate-hexane gave white prism crystals (13.2 g, yield 95percent). melting point: 94-95°C.Production Example 13-1 (0.01 mol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was added to a 50 ml three-necked flask, 2.9 ml (0.02 mol) of triethylamine, Dichloromethane. The solution was cooled to 0 ° C and slowly added dropwise with methanesulfonyl chloride (0.01 ml).After completion of the reaction, the reaction was continued for 2 hours at 0 ° C. The TLC assay (PE: EA = 2: 1) disappeared and the reaction was stopped. The organic layer was washed with water until neutral, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure to give 2.65 g (95.5percent) of a white solid, which was recrystallized from ethanol to give a white solid. .To a mixture of commercially available tert-butyl 4-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) and MsCl (854 mg, 7.46 mmol) in DCM (20 mL) was added EtPREPARATION 71 Step A: Reference Synthesis of 4-(methylsulfonyl)piperidine; (Step 1); tert-Butyl 4-hydroxypiperidine-1-carboxylate (2.5 g, 12 mmol) and triethylamine (2.1 mL, 15 mmol) were dissolved in dichloromethane (30 mL). To the solution was added a solution of methanesulfonyl chloride (1.2 mL, 15 mmol) in dichloromethane (10 mL), followed by stirring for 4 hours, while the temperature was raised to room temperature. To the reaction mixture was added water (50 mL), and the mixture was stirred for 30 minutes, followed by liquid separation. The organic layer was washed successively with 0.50 mol/L hydrochloric acid (40 mL x 2) and a saturated aqueous solution of sodium hydrogencarbonate (10 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting residue was added a mixed solvent of ethyl acetate and hexane (15 mL, ethyl acetate/hexane = 1/2), and the precipitated solid was filtered to obtain tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (3.1 g, 90percent). EXAMPLE 16a; Preparation of intermediate 4-methanesulfonyloxy-piperidine-1-caboxylic acid tert-butyl ester; To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2 g, 20 mmol) and DMAP (3 g, 24 mmol) in DCM (50 mL) was dropped methanesulfonyl chloride (2.7 g, 24 mmol) in ice bath. The reaction mixture was stirred for 2 h at room temperature. Then the mixture was filtered and washed by 0.5N HCl (50 mL), 1N NaTo a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2 g, 9.94 mmol) in THF was added triethylamine (6.94 ml, 49.7 mmol) at 0° C. Methanesulfonyl chloride (0.92 ml, 11.9 mmol) was added drop wise at 0° C. and the resulting mixture was stirred overnight at room temperature. The mixture was then concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate and concentrated to afford 2.5 g (90.3percent) of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester. To a solution of t-butyl 4-hydroxy-1-piperidinecarboxylate (0.94 g, 4.66 mmol) and methanesulfonyl chloride (0.43 ml, 5.56 mmol) in 10 ml of anhydrous CHTriethylamine (1.4 ml, 10 mmol) was added to a stirred solution of ter-butyl [4-HYDROXY-1-PIPERIDINE-CARBOXYLATE] (2.0 g, 9.94 mmol) in dichloromethane (40 ml) [AT-17°C] under nitrogen. [METHANESULFONYL] chloride (0.85 ml, 11 mmol) was added dropwise and the mixture allowed to warm up to room temperature overnight. The reaction mixture was diluted with dichloromethane (50 ml) and water [(100ML)] was added. The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (2 x 50 ml). The combined organic layers were dried [(MGSO4)] and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 50percent ethyl acetate in iso- hexanes to give ter-butyl [4-METHANESULFONYLOXY-PIPERIDINE-1-CARBOXYLATE] as a colourless oil (2.47 g, 89percent), [8N] (360MHz, [CDC13)] 1.46 (9H, s), 1.75-1. 88 (2H, m), 1.90-2. 00 (2H, [M), ] 3.04 (3H, s), 3.25-3. 35 (2H, [M), ] 3.65-3. 75 (2H, [M), ] 4.88 [(1H, ] m).Step A: tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0089) (0090) To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (550 mg, 2.5 mmol) and DMAP (296 mg, 2.5 mmol) in dichloromethane, (15 mL) cooled to 0°C by ice/water bath was added methanesulfonylchloride (189 µL, 2.5 mmol) and the resulting mixture stirred for 10 min at 0°C and then for an additional hour at RT. The mixture was quenched with ice water and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue oil was purified via silica gel preparative plates (3 x 1000 mM) eluting with 50percent ethyl acetate in hexane to afford the title compound (555 mg, 89percent). ESI-MS calculated for C1.53 kg of compound (CZT-6) was dissolved in 10 liters of dry dichloromethane, protected with nitrogen and slowly added to 2.5 litersTriethylamine, Keep the system temperature below20 degrees.After completion of the addition, the temperature was reduced to -10 degrees, slowly adding 1.05 liters of methylsulfonyl chloride, Keep the temperature below 5 degrees, after the completion of heating to room temperature reaction for 1 hour. Add 5 liters of water, stir for 30 minutes after the liquid, organicThe mixture was dried over anhydrous sodium sulfate, concentrated by filtration and recrystallized to give 1.8 kg of a white solid compound (CZT-7) in a yield88percentTo a cooled (5 - 10 ° C) mixture of N-Boc-4-hydroxypiperidine (25.0 g, 124 mmol) and triethylamine (19.6 ml, 136 mmol) in toluene (120 ml) was added slowly methanesulfonyl chloride (10.6 ml, 136 mmol) via a syringe. The rate of the addition was kept at such rate that the temperature of the reaction mixture did not rise above 20° C. After completion of the addition, the temperature was kept at room temperature for one and a half hours. Water (50 ml) was added to the mixture, and an emulsion formed that was broken by the addition of 100 ml toluene. The aqueous layer was extracted with 100 ml toluene and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness, leaving a white solid residue identified as the product (30.5 g, 87percent), and which was used as such in the next step.To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (3.0 g, 14.9 mmol) in DCM (30 mL) was added triethylamine (4.5 g, 44.8 mmol). To this mixture methane sulfonyl chloride (5.1 g, 44.8 mmol) was added dropwise. After addition, the mixture was stirred at 25 °C for 3 h and then filtered. The filtrate was washed with aqueous HC1, dried over NaTo a stirred solution of 4-hydroxy N-Boc-piperidine (8.0 g, 39.7mmol) and TEA (14 mL, 99.3 mmol) in DCM (80 mL), methane sulfonyl chloride (3.6 mL, 47.6 mmol) was added dropwise at 0 °C and the mixture was stirred for 2 h at rt. The completion of the reactionwas monitored by TLC. The reaction mixture was quenched with water. The organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The resulting title product was taken for the next step without any further purification. Yield:85percent (9.9 g, pale brown oil). 1H NMR (400 MHz, DMSO-d6): 6 4.85-4.81 (m, I H), 3.64-3.60 (m, 2H), 3.20 (s, 3H), 3.18-3.16 (m, 2H), 1.94-1.89 (m, 2H), 1.64-1.50 (m, 2H), 1.40 (s, 9H).LCMS: (Method A) 180.0 (M-boc), Rt. 2.63 mm, 99.8percent (ELSD).To a solution of intermediate 22 (200 g, 1.0 mol) and Et3N (204 g, 2.0 mol) in CH2Cl2 (3000 mL) was added dropwise a solution of MsCl (130 g, 1.14 mol) in CH2Cl2 (500 mL) under ice cooling. After the addition completed, the resulting mixture was stirred at room temperature for 24 h. Upon completion, the reaction mixture was washed with water and IN aqueous HCl (1000 mL). The organic layer was dried over MgSO4, and concentrated to give the title intermediate (230 g, 82percent) as a white solid.4-[4-(3, 5-Di-tert-butyl-4-hydroxy-phenylsuIfanyl)-piperidine-l-sulfonyl]- 3, 5-dimethyl-l//-pyrrole-2-carboxylic acidEx. 3a.; To a solution of 4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (40 g, 0.20 moles) in dichloromethane (800 mL) was added triethylamine (83.1 mL, 0.60 moles). The reaction was cooled to 0 °C. Methanesulfonyl chloride (23.1 mL, 0.30 moles) was added slowly over 15 minutes and the reaction was stirred at 0 To a stirred solution of 4-hydroxy-N-boc piperidine (1 g, 5.0 mmol, ABCR Ltd.) in DCM(25 mL) at 0 00 was added triethyl amine (754 mg, 7.5 mmol, Spectrochem) andmethane sulfonyl chloride (683 mg, 6.0 mmol, Spectrochem). Reaction mass was brought to RT and stirred for 2h. Reaction mass diluted with DCM, washed with water, saturated aqueous sodium bicarbonate solution, brine solution. The organic layer was dried over anhydrous sodium sulfate and evaporated. The crude product was isolated as off white solid and was taken for next step without any further purification (1.1 g, 79percent).1H NMR (400 MHz, 0D013): 64.93-4.85 (m, 1H), 3.75-3.67 (m, 2H), 3.35-3.26 (m, 2H), 3.04 (s, 3H), 2.02-1.95 (m, 2H), 1.92-1.85 (m, 2H), 1.46 (s, 9H). LCMS: (Method A)180.0 (M-Boc-fH), Rt. 0.7 mm, 99.7percent (ELSD).To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.50 g, 22.4 mmol, 1.0 eq) and TEA (11.3 g, 5.0 eq) in DCM (30.0 mL) at 0° C. was added MsCl (5.10 g, 44.5 mmol, 2.0 eq) in DCM (10.0 mL) dropwise. The resulting mixture was stirred at 0° C. for 30 min and then warmed to room temperature with stirring for 3 hr. After being quenched with water and extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over MgSOStep A: 4-Methanesulfonyloxy -piperidine- 1 -carboxylic acid tert-butyl esterTo a solution of the tert-butyl 4-hydroxy-piperidine- 1 -carboxylate (5.00 g, 24.9 mmol) in dichloromethane (50 mL) is added pyridine (10.00 mL, 122.6 mmol) and DMAP (0.56 g, 4.60 mmol). The mixture is then cooled to 0 To a mixture of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (19.0 g, 0.095 mol) in DCM (200 mL) was added TEA (19.19 g, 0.19 mol) and MsC1 (21 g, 0.19 mol) at 0 °C slowly. The reaction mixture was allowed to warm to room temperature overnight. The mixture was washed with H20 (100 mLx3) and extracted with DCM (200 mLx3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-methanesulfonyloxy- piperidine-1-carboxylic acid tert-butyl ester (20 g, yield 76percent) as a yellow solid. ‘H NIVIR (400 IVIHz, CDC13): ö = 4.89-4.88 (m, 1H), 3.72-3.67 (m, 2H), 3.33-3.29 (m, 2H), 3.27 (s, 3H), 1.97-1.94 (m, 2H), 1.84-1.79 (m, 2H), 1.46 (s, 9H).To a solution of commercially available tert-butyl 4-hydroxypiperidine-1 - carboxylate (4.02 g, 20 mmol) was dissolved in DCM (50 mL) andtriethylamine (3.03 g, 30 mmol) was added into the reaction mixture, then M5CI (2.51 g, 22 mmol) was added into the reaction mixture slowly at 000.The reaction mixture was stirred at r.t for 3 hours. The reaction mixture was quenched with water and extracted with DCM, dried over Na2SO4 andconcentrated under vacuo to give KR-36 (4 g, 71 .2percent). ESI-MS (Mi-i): 294calc.f0rC12H23NO5S: 293.13.To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) in DCM (50 mL) was added DIEA (2.00 g, 15.47 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and MsCl (862 mg, 7.53 mmol). The compound 1-2 (15.0 g, 74.6 mmol) and triethylamine (21 mL, 153 mmol) were dissolved in dichloromethane (200 mL) and methylsulfonyl chloride (6.0 mL, 74.6 mmol) was slowly added dropwise at 5 ° C The temperature was allowed to react at 5 to 15 ° C for 30 minutes.After the end of the reaction, the temperature was changed to room temperature, diluted with 400 mL of water and extracted with dichloromethane.The organic phase was washed twice with sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give compound 1-3 (13.0 g) in a yield of 62.0percent.hod L:Example L-1 : 4-(4-Acryloylamino-benzenesulfonyl)-piperidine-1 -carboxylic acid tert-butyl ester 4-Methanesulfonyloxy-piperidine-1 -carboxylic acid tert- butyl ester [00527] Methane sulfonyl chloride (0.46ml, 2.9mnnol) was added dropwise to a cool (0°C) solution of te/t-butyl 4-hydroxy-1 -piperidinecarboxylate (1 .0g, 4.97mnnol) and triethylamine (0.83ml, 10.9mmol) in THF (10ml) and the mixture was stirred at 0°C under a nitrogen atmosphere for 3 hours. After this time, the mixture was diluted with ethyl acetate (50ml) and washed sequentially with HCl (1 M solution, 20ml), NaHCOThe 4-hydroxypiperidine (3g, 29.7mmol) was dissolved in dichloromethane (100mL), theTo a solution of triethylamine (7.52 g, 74.3 mmol)Dibutyl dicarbonate (6.81 g, 31.2 mmol) was added dropwise, The reaction was completed at 25 ° C for 16 hours, TLC (dichloromethane: methanol = 20: 1) detection reaction is completed, Cooling to 0 , A solution of methanesulfonyl chloride (3.74 g, 32.67 mmol)The reaction was completed at 25 ° C for 3 hours.TLC (petroleum ether: ethyl acetate = 1: 1) detection reaction is completed, Add water (100 mL), Dispensing, The organic phase was dried over anhydrous sodium sulfate, Concentrated in vacuo to give the product (7.1g, yield 85.6percent).Step APart B: Part B: Part B: Part B: Part B: Part B: Part B: 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2)

Molecular Weight:279.36
XLogP3:1.1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:279.11404394
Monoisotopic Mass:279.11404394
Topological Polar Surface Area:81.3
Heavy Atom Count:18
Complexity:385
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes