1-BENZYL 4-ETHYL PIPERIDINE-1,4-DICARBOXYLATE

A solution of benzyl chloroformate (95g, 0. 56mol) in dichloromethane (200ml) was added dropwise to an ice-bath-cooled, stirred mixture of ethyl isonipecotate (87G, 0. 55MOL), sodium carbonate (60g, 0. 57mol) and dichloromethane (200ml) over 70 minutes. The mixture was stirred at ambient temperature for 2.5 days and filtered though a pad of Celte. The filtrate was concentrated in vacuo. The residue was partitioned between 2M aqueous hydrochloric acid and diethyl ether. Organic layer was separated, dried (MGS04), filtered and concentrated. The residue was chromatographed on silica gel (ethyl ACETATE/ISO-HEXANE) to give the title product (152g, 94percent). lE NMR (360 MHz, CDCl3) : 5 7. 4 1-7. 27 (5H, M), 5.12 (2EI, s), 4.22-3. 99 (2H, M), 4. 14 (2H, Q, J7. 4HZ), 2.93 (2H, br T, J 11. 6HZ), 2.45 (2H, m), 1.97-1. 81 (2H, M), 1.74-1. 56 (2EI, m), 1. 25 (3H, T, J7. 4Hz).EXAMPLE 38; 2-{1-[(dimethylamino)sulfonyl]-4-methylpiperidin-4-yl}-1H-benzimidazole-4-carboxamide; EXAMPLE 38A; 1-benzyl 4-ethyl piperidine-1, 4-dicarboxylate A solution of ethyl piperidine-4-carboxylate (30 g) in 1:1 THF/water (300 mL) was treated with cesium carbonate (74.5 g) and benzyl chloroformate (32.2 mL) and stirred at room temperature for 18 hrs. The reaction mixture was partitioned between ethyl acetate and water and the organics concentrated. The residue was purified by flash chromatography (silica gel, ethylacetate/hexanes) to provide Example 38A (50.87 g, Yield: 92percent). MS (DCI/NHPiperidine-1 , 4-dicarboxylic acid 1 -benzyl ester 4-ethyl ester (1); Ethyl 4-piperidinecarboxylate (99.48 g, 632, 78 mmol) and pyridine (56.8 g, 696 mmol) were dissolved in dichloromethane (800 ml_) and cooled to 04-Ethoxycarbonylpiperidine (1.572 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); triethylamine (2.79 ml, 20.0 mmol) and benzyl chlorocarbonate (1.71 ml, 12.0 mmol) were added dropwise while cooled with an ice water bath; and the reaction mixture was stirred at room temperature overnight. Ethyl piperidine-4-carboxylate (3.0 g, 19.1 mmol) was dissolved in THF (15 mL) and Cs2CO3 (7.4 g, 22.9 mmol) added at OC. The resulting reaction mixture was stirred at 0 - 5°C for 10 mins, then benzyl chloroformate (3.2 g, 19.1 mmol ) was added dropwise, and the reactionmixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between H20 (100 mL) and EtOAc (200 mL), the aqueous layer was extracted with EtOAc (2 x 200 mL), the organic layers were combined, dried (Na2SO4) and the solvent was removed in vacuc. The residue was purified by column chromatography (Normal silica, mesh size: 60-120, 0percent to 10percent EtOAc in Hexane) to give 1-benzyl 4-ethyl piperidine-1, 4-dicarboxylate (4.2 g, 76.4percent) as ayellow solid.Method AA: 1-benzyl 4-ethyl piperidine-1, 4-dicarboxylate Benzyl chloroformate (11.9 g, 70.0 mmol) was added dropwise to a solution of ethyl isonipecotate (13) (10.0 g, 63.6 mmol) and Et[0398] Benzyl chloroformate (29.5 mL) was added to a solution of ethyl piperidine-4-carboxylate (25.0 g) and diisopropylethylamine (55.5 mL) in THF (150 mL) at 0°C, and the resultant was stirred for 2 hours at 0°C. After an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture at room temperature, extraction thereof was performed using ethyl acetate. The obtained organic layer was sequentially washed with an aqueous saturated sodium hydrogen carbonate solution, 1 M hydrochloric acid and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column chromatography (NH, hexane/ethyl acetate), thereby obtaining the title compound (30.1 g). 1H NMR (400 MHz, CDC1

Molecular Weight:291.34
XLogP3:2.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:6
Exact Mass:291.14705815
Monoisotopic Mass:291.14705815
Topological Polar Surface Area:55.8
Heavy Atom Count:21
Complexity:344
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes