N-tert-Butoxycarbonyl-4-(4-toluenesulfonyloxymethy

(1) N-Boc-4- piperidinemethanol (0.1mol) was dissolved in 300ml of dichloromethane. Ice bath cooling to 10 deg.C. 20ml of triethylamine was added. Then, portionwise add p-toluenesulfonyl chloride (0.11 mmol ). After addition was complete, react at room temperature for 12h. Completion of the reaction, the reaction solution was washed with water, saturated sodium bicarbonate solution, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was passed through the column (eluent PE: EA = 1: 1) as a colorless oil was 34g, 92.1percent yield, Synthesis l, l-dimethylethyI 4-{[(2-{[(4-{[(2, 4-dimethylphenyI)amino]carbonyl}- lH-imidazol-S-y^carbonyljaminoj-lH-benzimidazol-S-yOoxylmethyljpiperidine-1-carboxylate; Synthesis of tert-Butyl 4-(tosyloxymethyl)piperidine-l-carboxylate; [00183] 4-Hydroxylmethyl-N-(tert-butylcarboxylate)piperidine (10.76 g, 50 mmoles, 1 equivalent, commercially available from Aldrich) was dissolved in anhydrous pyridine (40ml) and cooled to 0 Preparation intermediate 11tert-Butyl 4-(tosyloxymethyl)piperidine-l-carboxylateTo a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine- l- carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mL) at 0°C under nitrogen, /?-toluenesulfonyl chloride (4.87 g, 25.55 mmol) was added in one portion. The reaction was stirred at 0°C for 100 minutes before warming to RT. After 18 hours the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with aqueous hydrochloric acid (2 100 mL, 1.0 M solution), saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo to yield the title compound (7.87 g, 91percent). NMR (400 MHz, CDClTo a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mL) at 0° C. under nitrogen, p-toluenesulfonyl chloride (4.87 g, 25.55 mmol) was added in one portion. A stirred solution of tert-butyl 4-(hydroxymethyl) piperidine-1-carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mE) at 0° C. under nitrogen was added with p-toluenesulfonyl chloride (4.87 g, 25.55 mmol) in one portion. The reaction was stirred at 0° C. for 100 minutes before warming to room temperature. Afier 18 hours the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic extracts were washed with aqueous 1M hydrochloric acid (x2), brine, dried (magnesium sulfate), filtered and evaporated under reduced pressure to yield the title compound as a yellow solid (7.87 g, 9 1percent). 1H NMR (400 MHz, CDC13): ö 7.78 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.15-4.07 (m, 2H), 3.85 (d, J=6.5 Hz, 2H), 2.68-2.60 (m, 2H), 2.46 (s, 3H), 1.88-1.78 (m, 1H), 1.66-1.59 (m, 2H), 1.44 (s, 9H), 1.16-1.04 (m, 2H).A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (50 g, 232.25 mmol, 1.00 equiv), triethylamine (35.2 g, 347.86 mmol, 1.50 equiv), 4-dimethylaminopyridine (2.8 g, 22.92 mmol, 0.10 equiv) and 4-methylbenzene-1-sulfonyl chloride (53 g, 278.00 mmol, 1.20 equiv) in CHTo a mixture of 5 (5.7 g, 26.4 mmol), DMAP (0.16 g, 1.3 mmol) in pyridine (15 mL, 186 mmol) cooled to 0-5 °C (ice-bath), tosyl chloride (5.3 g, 27.8 mmol) was added in portion over a period of 15 min. After addition the reaction mixture was stirred at room temperature for 5 h and then poured into ice water (150 mL). The resulting mixture was extracted with EA (2 × 120 mL), the combined organic extracts was washed with dilute hydrochloric acid (1 N, 3 × 100 mL), saturated NaHCOTo a mixture of 4 (5.7 g, 26.4 mmol), DMAP (0.16 g, 1.3 mmol) in pyridine (15 mL, 186 mmol) cooled to 0-5 °C (ice-bath), tosyl chloride (5.3 g, 27.8 mmol) was added in portion over a period of 15 min. After addition the reaction mixture was stirred at room temperature for 5 h and then poured into ice water (150 mL). The resulting mixture was extracted with EA (2 × 120 mL), the combined organic extracts was washed with dilute hydrochloric acid (1 N, 3 × 100 mL), saturated NaHCO1, 4-Diazabicyclo [2.2. 2] octane (42.4 g, 0.378 mol) was added to a solution OF 4- HYDROXYMETHYL-1-TERT-BUTYLOXYCARBONYLPIPERIDINE (52.5 g, 0.244 mol) in tert-butyl methyl ether (525ML) and the reaction stirred at ambient temperature for 15 minutes. The reaction was cooled to 5 °C and a solution of 4-toluenesulphonyl chloride (62.8 g, 0.33 mmol) in tert-butyl methyl ether (525 ml) was added dropwise over 2 hours while maintaining the temperature at 0 °C. The reaction was stirred at ambient temperature for 1 hour, isohexane was added and the resultant precipitate was collected by suction filtration. Solvent evaporation in vacuo afforded a solid which was dissolved in diethyl ether (250 ml) and washed successively with 0.5 N aqueous hydrochloric acid (2 x 500 ml), water, saturated sodium hydrogen carbonate and brine. Solvent evaporation and drying in vacuo yielded 4- (4-METHYLPHENYLSULPHONYLOXY- METHYL)-L-TERT-BUTYLOXY-CARBONYLPIPERIDINE (76.7g, 85 percent yield) as a white solid: 'H NMR (CDC13) : 7.80 (d, 2H), 7.35 (d, 2H), 4.00-4. 20 (s, 2H), 3.85 (d, 1H), 2.55-2. 75 (m, 2H), 2.45 (s, 3H), 1.75-1. 90 (M, 2H), 1.65 (d, 2H), 1.45 (s, 9H), 1.00-1. 20 (m, 2H) : MS (+ve ESI): 392 (M+Na) +1, 4-Diazabicyclo[2.2.2]octane (42.4g, 0.378mol) was added to a solution of 4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (52.5g, 0.244mol) in tert-butyl methyl ether (525ml). 1, 4-Diazabicyclo[2.2.2]octane (42.4g, 0.378mol) was added to a solution of 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (52.5g, 0.244mol) in tert-butyl methyl ether (525ml). To a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1 -carboxylate (I-47) (60 g, 46 mmol) and TEA (42.3 g, 418 mmol) in CH2CI2 (300 mL) was added TsCI (55.8 g, 293 mmol) in portions at 0~5 °C. The resulting mixture was stirred at 15 °C for 12 h. TLC (petroleum ether/EtOAc=3:1 , Rf ~0.7) showed that the reaction was completed. The reaction mixture was washed with saturated NaHC03 (3 x 300 mL) and brine (3 x 300 mL).The organic phase was dried over Na2S04, filtered and concentrated in vacuo to give the crude product, which was stirred in petroleum ether (50 mL) for 10 min and then filtered, dried in vacuo to obtain tert-butyl 4-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1 -carboxylate (I-85) (80 g, 78percent) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 7.77 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 4.08 (br. s., 2 H), 3.84 (d, J = 6.4 Hz, 2 H), 2.45 (s, 3 H), 1 .81 - 1 .83 (m, 1 H), 1 .61 - 1 .69 (m, 2 H), 1 .43 (s, 9 H), 1 .06 - 1 .14 (m, 2 H).A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (4.0 g, 18.6 mmol), tosyl chloride (4.25 g, 22.3 mmol), TEA (5.4 mL, 37.2 mmol), DMAP (568 mg, 4.65 mmol) in DCM (64 mL) and THF (16 mL) was stirred at 40° C. overnight. The reaction mixture was then concentrated, diluted with EtOAc (100 mL), and washed with an aqueous HCl solution (0.5 M, 40 mL) and then brine (2×50 mL). The organic layer was dried (MgSOTert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate 5a (2.15 g, 10 mmol) (Shaoyuan Chemical, SY005902), triethylamine (2.77 mL, 20 mmol), 4-dimethylaminopyridine (122 mg, 1 mmol)Dissolved in 30 mL of methylene chloride, P-Toluenesulfonyl chloride (2.86 g, 15 mmo 1) was added and reacted for 16 hours. To the reaction mixture was added 50mL water, liquid separation, aqueous useThe organic layer was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system C The title product 4_ (tolueneSulfonate) piperidine-1-carboxylate 5b (2.6 g, pale yellow solid), yield: 70.5percent.General procedure: Boc-piperidinemethanol (27) or Boc-piperidineethanol (28) (23 mmol) dissolved in pyridine (50 mL) and cooled down under nitrogen. Then a tosyl chloride (27, 87 mmol) was added portionwise. The was carried out for 3 h on bath-ice, then warm to room temperature and stirred for additional 10 h. The reaction mixture was extracted with CHtert-Butyl-4-(hydroxymethyl)piperidine-1-carboxylate (1 g, 4.64 mmol) was stirred in pyridine (3.7 mL) at 0 °C. p-Toluene sulfonyl chloride (0.974 mg, 5.11 mmol) was added in one batch under nitrogen and the mixture stirred for 100 minutes at 0 °C. The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was poured onto water (25 mL) and extracted with ethyl acetate (3 15 mL). The organic layer was washed with 1M HCl (15 mL) and brine (15 mL), dried over MgSO4-Methylbenzene-1-sulfonyl chloride (13 g, 67.5 mmol, 1.10 equiv) and triethylamine (12 g, 118 mmol, 2.00 equiv) were added to a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (13 g, 54.3 mmol, 1.00 equiv) in dichloromethane (200 mL). Synthesis of tert-butyl 4-(tosyloxymethyl) piperidine-1-carboxylate Reaction Step 1

Molecular Weight:369.5
XLogP3:3.2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:369.16099414
Monoisotopic Mass:369.16099414
Topological Polar Surface Area:81.3
Heavy Atom Count:25
Complexity:533
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes