Ethyl N-Boc-piperidine-4-carboxylate

Liquid

Piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester To a stirred solution of ethyl piperidine-4-carboxylate hydrochloride (12.0 g, 62.33 mmol) in DCM (200 mL) was added TEA (18.92 g, 187.01 mmol) dropwise at room temperature and reaction allowed to stir for 15 min. After 15 min Boc anhydride (20.40 g, 93.50 mmol) was added it and stirred for 16 h. Reaction was monitored by TLC. On completion reaction was quenched with water, extracted with DCM. The organic layer was washed with water, NaHCOTo a solution of ethyl isonipecotate (5.00 g, 0.032 mol) and triethylamine (4.9 [ML, ] 0.035 mmol) in dichloromethane (25 mL) at [0°C] was slowly added a solution of di-tert-butyldicarbonate (7.2 g, 0.033 mol) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature overnight, then washed with potassium hydrogen sulfate three times and with brine once. The organic extract was-dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give the desired product (8.23 g, 100percent) as colorless [OIL. 1H] NMR [(C6D6, ] 500 MHz) [5] 3.88 (q, J = 7.5 Hz, 2H), 2.52 (m, 1H), 1.60-1. 48 [(M, ] 8H), 1.42 (s, 9H), 0.92 (t, 3H). Mass spec.: 280.44 (M+Na) [+.]Step 1: JV-Boc ethylisopinecotateBocA mixture of ethyl isonipecotate (5.00 g, 31.8 MMOL), di-tert-butyl dicarbonate (7.64 g, 34.99 MMOL), and sodium carbonate (6.74 g, 63.6 mmol) in water/tetrahydrofuran (50 mL: 20MOL) was heated at reflux for 2 hours. The mixture was allowed to cool to room temperature, and was extracted with ethyl acetate (2 X 200 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. A thick yellow oil was afforded, 8.17 g (99.8percent). MS (APCI) (M+L)/Z 258, (M-BOC + l)/z, 157.9.[0160] To a solution of ethyl isonipecotate (0.750 g, 4.77 mmol) in THF (24 mL) was added water (1 mL) followed by di-tert-butyl dicarbonate (1.09 g, 5.00 mmol) and the resultant mixture was stirred at room temperature for one hour. The mixture was diluted with ethyl acetate (50 mL) and the organic phase was washed with brine (3.x.20 mL), dried (MgSO4), and concentrated to provide 1.20 g (98percent) of 1-(tert-butoxycarbonyl)-4-(carboethoxy)-piperidine as a colorless oil. [0161] To a cold (-78° C.), stirred solution of the oil from above (1.20 g, 4.67 mmol) in dry THF (46 mL) was added diisobutylaluminum hydride (1.0 M in THF, 15 mL, 15 mmol). After 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 20 minutes. Saturated aqueous NH4Cl (5 mL) was added and the resultant white slurry was stirred at room temperature for 45 minutes. Solid MgSO4 (5 g) was added and the mixture was filtered through Florisil..(C). The column was washed with ethyl acetate (200 mL). The combined eluant was concentrated under reduced pressure to provide 1.01 g (97percent) of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)-piperidine as a white solid. [0162] To a solution of the above alcohol (0.437 g, 2.03 mmol) in CH2Cl2 (10 mL), at room temperature, was added sequentially 3 molecular sieves (1.07 g), N-methylmorpholine N-oxide (0.365 g, 3.11 mmol), and tetrapropylammonium perruthenate (70 mg, 0.20 mmol). After 1 hour, the mixture was filtered through a short column of silica gel and the cake was washed with ethyl acetate. The solvent was removed from the filtrate under reduced pressure. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-ethyl acetate) provided 90 mg (20percent) of 1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde as a colorless oil. 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.51-1.62 (m, 2H), 1.85-1.93 (m, 2H), 2.37-2.46 (m, 1H), 2.88-2.97 (m, 2H), 3.94-4.00 (m, 2H), 9.66 (s, 1H). [0163] Using General Procedure B: Reaction of 1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde (0.090 g, 0.42 mmol) and (1H-benzimidazol-2-ylmethyl)-(5, 6, 7, 8-tetrahydro-quinolin-8-yl)-amine (0.110 g, 0.40 mmol) with NaBH(OAc)3 (0.223 g, 1.05 mmol) in CH2Cl2 (5 mL) for 20 h followed by purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-CH3OH-NH4OH) provided 0.120 g (63percent) of an off-white solid. [0164] Using General Procedure D: Conversion of the off-white solid (120 mg) to the hydrobromide salt with simultaneous removal of the BOC-protecting group, followed by re-precipitation of the intermediate solid from methanol/ether, gave COMPOUND 6 (98 mg) as a white solid. 1H NMR (D2O) δ 1.13-1.28 (m, 2H), 1.80-2.36 (m, 8H), 2.81-3.00 (m, 5H), 3.35-3.43 (m, 2H), 4.38 (d, 1H, J=16.5 Hz), 4.46 (d, 1H, J=16.5 Hz), 4.52 (dd, 1H, J=10.5, 6.0 Hz), 7.59-7.65 (m, 2H), 7.78-7.85 (m, 2H), 7.89 (dd, 1H, J=7.8, 6.0 Hz), 8.37 (d, 1H, J=8.1 Hz), 8.67 (d, 11H, J=5.7 Hz); 13C NMR (D2O) δ 17.72, 18.24, 24.98 (2 carbons), 25.71, 29.64, 41.94, 42.05, 45.79, 54.96, 57.53, 112.25, 124.08, 125.04, 128.97, 137.47, 139.09, 146.24, 148.75 (2 carbons); ES-MS m/z 376 (M+H). Anal. Calcd. for C23H29N5.3.1 HBr.1.8H2O: C, 41.93; H, 5.46; N, 10.63; Br, 37.60. Found: C, 42.07; H, 5.55; N, 10.28; Br, 37.43.To a solution of ethyl isonipecotate (50 g, 0.318 mol) in CH2Cl2 (150 mL) at 0° C. was added a solution of di-t-butyl dicarbonate (73 g, 0.334 mol) in CH2Cl2 (150 mL) over 15 min. The ice bath was removed and the reaction mixture was stirred at rt for 12 h. The solvent was evaporated to yield a liquid. Subsequent purification by sgc (4:1 hexanes-Et2O) gave 80 g (98percent) of Compound 18.A solution of di-tert-butyl dicarbonate (41.7 g, 0.19 mol) in ethyl acetate (75 ml) was added dropwise to a solution of ethyl 4-piperidinylcarboxylate (30 g, 0.19 mol) in ethyl acetate (150 ml) while maintaining the temperature in the range 0-5 °C. The reaction was stirred at ambient temperature for 48 hours, poured onto water (300 ml) and the organic layer was separated and washed with i) water (200 ml), ii) 0. 1N aqueous hydrochloric acid (200 ml), iii) saturated sodium hydrogen carbonate (200ML) and iv) brine (200ML). Evaporation and drying in vacuo yielded ethyl (L-TEJT-BUTYLOXYCARBONYLPIPERIDIN-4-YL) carboxylate (48 g, 98 percent yield) as a white solid: 1H NMR (CDCl3) : 4.15 (q, 2H), 3.91-4. 10 (s, 2H), 2.70-2. 95 (t, 2H), 2.35-2. 50 (m, 1H), 1.80- 2.00 (d, 2H), 1.55-1. 70 (M, 2H), 1.45 (s, 9H), 1.25 (t, 3H)While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0. 19mol) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0. 19mol) in ethyl acetate (150ml) cooled at 5°C. After stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ML). The organic layer was separated, washed successively with water (200ML), O. 1N aqueous hydrochloric acid (200ML), saturated sodium hydrogen carbonate (200ML) and brine (200ml), dried (MGS04) and evaporated to give ethyl 4-(1-(TERT-BUTOXYVARBONYL) piperidine) carboxylate (48g, 98percent). H NMR Spectrum: (CDCl3) 1.25 (t, 3H); 1.45 (s, 9H); 1.55-1. 70 (m, 2H); 1.8-2. 0 (d, 2H); 2.35- 2.5 (m, 1H); 2.7-2. 95 (t, 2H); 3.9-4. 1 (br s, 2H); 4.15 (q, 2H)While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0. 19MOL) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0. 19MOL) in ethyl acetate (150ML) cooled at 5°C. After stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ML). The organic layer was separated, washed successively with water (200ML), 0. IN aqueous hydrochloric acid (200ML), saturated sodium hydrogen carbonate (200ML) and brine (200ML), dried (MGS04) and evaporated to give ethyl 4-(1-(TERT-BUTOXYZARBONYL) piperidine) carboxylate (48g, 98percent). LH NMR SPECTRUM : (CDC13) 1.25 (t, 3H); 1.45 (s, 9H); 1.55-1. 70 (m, 2H); 1. 8-2.0 (d, 2H) ; 2.35- 2.5 (m, 1H); 2.7-2. 95 (t, 2H) ; 3.9-4. 1 (br s, 2H); 4.15 (q, 2H)A solution of di-tert-butyl dicarbonate (41.7g, 0.19mol) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0.19mol) in ethyl acetate (150ml) cooled at 5°C, while maintaining the temperature in the range 0-5°C. While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0.19mol) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0.19mol) in ethyl acetate (150ml) cooled at 5°C. General procedure: A solution of commercially available substituted piperidinederivative (12.7 mmol) in anhydrous DCM (100 mL) wascooled to 0 °C. Tert-butyldicarbonate (2.6 g, 12.1 mmol) inDCM (20 mL) was added drop-wise into solution. After beingstirred for 10 min, the reaction mixture was allowed to adjustto room temperature and stirred overnight. After dilutionwith water, the crude product was extracted with DCM (100mL×2). The combined organic extracts were washed withhydrochloric acid (0.5 mol/L, 50 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated to yield compounds2a and 15a. The crude product was used without furtherpurification.Piperidine-1 , 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1); Di-te/t-butyl dicarbonate (5.25 g, 23.8 mmol) was added to a solution of ethyl 4- pipehdinecarboxylate (2.5 g, 15.9 mmol) and potassium carbonate (4.4 g, 31.8 mmol) in dioxane/water (2:1 , 90 ml_) and stirred over night. The dioxane was evaporated and the aqueous phase was extracted with ethyl acetate (4 x 40 ml_). The combined organic layers were washed with brine, dried over sodium sulphate, filtrated and evaporated to give piperidine-1 , 4-dicarboxylic acid 1 -fe/t-butyl ester 4-ethyl ester (4.76 g) as the crude product. Flash chromatography with ethylacetate-heptane as eluent gave piperidine-1 , 4-dicarboxylic acid 1 -fe/t-butyl ester 4-ethyl ester (3.99 g 98percent)Preparation 49: 1-tert-butyl 4-ethyl 14-piperidinedicarboxVLate To a solution of ethyl 4-piperidinecarboxylate (15.4 ML, 0.1 mol) in dichloromethane (100 ML) stirred under nitrogen and cooled to 0 C was added di-tert-butyl dicarbonate (21.5 g, 0.1 mol). The reaction mixture was stirred at room temperature for 18 h before washing with water and then saturated brine. The organic extracts were dried (NA2SO4) and concentrated in vacuo to give the title compound as an oil (25 g, 97percent).Step 1: This reaction was conducted in a jacketed, 49 L reactor equipped with a retreat curve agitator, nitrogen purge system, and condenser system. The reactor was charged with di-t-butyl dicarbonate (1) in tetrahydrofuran (THF) (75percent, 4.674 Kg, 16.06 mol) and tetrahydrofuran (5.50 Kg, 76.3 moles). After cooling the mixture to 0° C., ethyl isonipecotate (2) (2.500 Kg, 15.90 mol) was charged to the reactor while maintaining the contents at a temperature of from 0 to 15° C. After all the ethyl isonipecotate was added, the contents were warmed to 25° C., and then stirred for 2 hours at that temperature. The mixture was then cooled to 0° C. The THF was then removed by vacuum distillation until the batch temperature reached 80° C. Afterward, the contents were cooled to 25° C. This yielded 3.99 Kg of product in the form of an amber oil. The concentration of the Boc-20 protected ethyl isonipecotate (3) was 96.3percent (by weight). [TABLE-US-00001] TABLE 1 Reaction Summary for Part A volume MW equiv. wt (kg) moles density (g/mL) (L)materials compound (1) (75percent) 218.25 1.01 4.674 16.06 0.913 5.12 tetrahydrofuran 72.11 4.8 5.50 76.3 0.889 6.19 compound (2) 157.21 1.00 2.500 15.90 1.020 2.45 product compound (3) 257.33 (1.00) (4.092) (15.90) The numbers in parenthesis in the above table are theoretical..Piperidine-4-carboxylic acid ethyl ester (3.14 g, 20 mmol) was dissolved in acetonitrile (25 mL). Di-t-butyldicarbonate (5.23 g, 24 mmol) was added and the reaction was stirred for 30 minutes. Polyamine scavenger resin was added and reaction mix was allowed to stand for 18 hours. The resin was filtered away and the volatiles were evaporated. The residue was chromatographed on silica gel with 0-25percent ethyl acetate in hexane. The title compound (4.88 g, 94percent) was isolated as a colorless oil. Step 1: A solution of ethyl [ISONIPECOTATE] (20.0 g, 127 mmol) and [DI-TERKBUTYL] dicarbonate (29.1 g, 134 mmol) in dry dichloromethane was stirred at room temperature for 1 hour and the solvent removed under reduced pressure to yield the BOC derivative as a colourless oil (31 g, 91percent). [ON] (360MHz, [CDCL3)] 1.26 (3H, t, J=7. [1HZ), ] 1.46 (9H, s), 1.61-1. 66 (2H, m), 1.85 (2H, m), 2.43 [(1H, ] [M), ] 2.83 (2H, m), 3.95-4. 05 (2H, m), 4.14 (2H, dd, J=7.1 and 14.2Hz).To a solution of ethyl isonipecotate (20 g, 127 mmol) in dioxane:water (1:1, 120 mlL) was added triethylamine (12.87 g, 127 mmol) at 0° C. followed by di-tert-butylcarbonate (35.2 g, 161 mmol) and the resulting mixture maintained at this temperature for 2 h. The product was then extracted with ethyl acetate (3.x.100 mL) and the combined organic extracts washed with HCl (1 N, 100 mL), brine (100 miL), dried over sodium sulfate, filtered and evaporated. Purification by Kugelrohr distillation afforded the title compound (29.0 g, 89percent) as a colourless liquid, bp 140° C. at 0.13 mbar. MS: m/e=275.2 (M+NH4).a) To a solution of ethyl isonipecotate (20 g, 127 mmol) in dioxane:water (1:1, 120 mL) was added triethylamine (12.87 g, 127 mmol) at 0° C. followed by di-tert-butyl dicarbonate (35.2 g, 161 mmol) and the resulting mixture maintained at this temperature for 2 h. The product was then extracted with ethyl acetate (3.x.100 mL) and the combined organic extracts washed with HCl (1 N, 100 mL), brine (100 mL), dried over sodium sulfate, filtered and evaporated. Purification by Kugelrohr distillation afforded the title compound (29.0 g, 89percent) as a colourless liquid, bp 140° C. at 0.13 mbar. MS: m/e=275.2 (M+NHAt about 0° C., di-tert-butyl dicarbonate (4.56 g, 20.92 mmol, 1.10 equiv) was added in several batches to a solution of ethyl piperidine-4-carboxylate (3.14 g, 19.97 mmol, 1.00 equiv) and ethyl acetate (40 mL). 1. Synthesis of intermediate B-1: A-1 B-1 To a solution of A-1 (100 g, 0.64 mol) and EtTo a solution of A-1 (100 g, 0.64 mol) and EtTo a solution of A-1 (100 g, 0.64 mol) and Et60 g (0.381 mol) of ethyl isonipecotate and 400 ml of THF are placed in a three-necked flask which is protected from moisture and which is under an inert atmosphere, and 18.3 g (0.458 mol) of sodium hydroxide pellets are added. A solution of 100 g (0.458 mol) of di-t-butyl dicarbonate in 170 ml of THF is added over 1 h with stirring to the suspension. The temperature reaches 45° C. The reaction mixture is left stirring for 14 h at 20-25° C. and is then poured onto 2 l of water and ice and extracted with 3 times 500 ml of ether. The organic phase is washed with 3 times 250 ml of a saturated NaCl solution, dried over Na2SO4 and concentrated. The residue is chromatographed by eluting with CH2Cl2 gradually enriched with acetone and then distilled under a vacuum of 0.09 mm Hg and at a vapour temperature of 95-102° C. 82 g are obtained (Yd=83.6percent). TLC (95/5 CH2Cl2/acetone): Rf=0.60. [0246] N.M.R.: CDCl3 1H ((ppm): 1.2-1.3 (t, 3H), 1.4 (s, 9H), 1.5-1.6 (m, 2H), 1.8-1.9 (m, 2H), 2.35-2.45 (m, 1H), 2.7-2.85 (m, 2H), 3.9-4.0 (m, 2H), 4.05-4.15 (q, 2H))Under ice-cooling, piperidine-4-carboxylic acid(20.0 g, 127 mmol), BoC2 (30 g, 140 mmol) was added toTHF (lOOmL) and triethylamine (19.2 g, 190 mmol) was slowly added dropwise.Add to the ice in the ice bath for 30 minutes, then heated to room temperature stirring overnight. The organic phase was washed with saturated brine, the organic phase was separated, dried and concentrated, and the crude product was purified by column chromatography (ΡΕ: ΕΑ = 10: 1). The organic phase was extracted with ethyl acetate and extracted with ethyl acetate.To give 1-tert-butyl-4-ethyl-piperidine-1, 4-dicarboxylic acidEster (26 g, yield 80percent)

Molecular Weight:257.33
XLogP3:1.8
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:257.16270821
Monoisotopic Mass:257.16270821
Topological Polar Surface Area:55.8
Heavy Atom Count:18
Complexity:301
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes