1-CBZ-2-PIPERIDINECARBOXYLIC ACID

White solid

10 g of 2-piperidine carboxylic acid into 250 ml four-necked flask, 80 gof 10percent aqueous sodium hydroxide solution, stirred and dissolved, and slowly addeddropwise 15.7 g of sodium hydroxide and 25 g of an aqueous solution of Cbz addeddropwise after completion of the reaction at room temperature for 12 hours. take 100grams of ether extract the aqueous layer with dilute hydrochloric acid to weak acid, andthen extracted three times, the organic layers combined, dried over magnesium sulfateand filtered, the organic layer was concentrated to give 19.6 g of dry product (singlestep yield 96.1percent).Intermediate 47. Synthesis of 2-(lH-pyrrolo[3, 2-b]pyridin-3-yl)-octahydro-lH-pyrido[l, 2- a]pyrazine.1. Synthesis of 1 -(benzyloxycarbonyl)piperidine-2-carboxylic acid.Benzyl chloroformate (78.5 mmol) was added dropwise to a solution of piperidine-2- carboxylic acid (77.5 mmol) in 2 M sodium hydroxide (39 mL) at 0 A. To a 100 mL roundbottom flask containing a stir bar was added 1- ((benzyloxy)carbonyl)piperidine-2-carboxylic acid (0.435 g, 1.6 mmol), followed by DCM 1 mL). The reaction mixture was stirred and the following reagents were added (in the order listed): TEA (0.417 mL, 0.303 g, 3.0 mmol), EDCI (0.342 g, 1.8 mmol), and DMAP (0.060 g, 0.50 mmol). Stirring commenced and the reaction vessel was sealed with a septa and flushed with nitrogen. To this mixture was added 3, 4, 5-trimethoxybenzyl alcohol (0.273 mL, 0.336 g, 1.7 mmol, dissolved in 2.0 mL DCM) via syringe. The reaction mixture was allowed to stir overnight. The following day, the reaction mixture was transferred to a separatory funnel and extracted with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude product as a clear oil. The crude material was purified by silica gel chromatograpy (1 :3 ethyl acetate: hexanes, R/= 0.28) to yield the final product as a clear oil (0.371 g, 50 %). NMR (500 MHz) (CDCL) (amide rotamers) d: 7.35 - 7.25 (5H, m), 6.55 - 6.52 (2H, m), 5.15 - 4.89 (5H, m), 4.14 - 4.03 (1H, m), 3.83 - 3.82 (9H, m), 3.11 - 2.96 (1H, m), 2.28 - 2.21 (1H, m), 1.70 - 1.41 (4H, m), 1.28 - 1.22 (1H, m). 13C NMR (125 MHz) (CDCb) (amide rotamers) d: 171.5, 156.4, 155.9, 153.3, 137.7, 136.5, 131.4, 131.2, 128.4, 128.4, 128.0, 127.7, 127.6, 104.9, 104.8, 67.3, 67.2, 66.8, 60.8, 56.1, 54.7, 54.4, 41.9, 41.8, 26.7, 24.7, 24.5, 20.7, 20.6. HRMS calc'd for [M+Na] =466.1842, observed = 466.1845. IR (NaCl, DCM): 2941, 1734, 1699, 1592, 1457, 1420, 1242, 1192, 1127.To a solution of 9.41 g (1 eq.) l-(Benzyloxycarbonyl)-2-piperidinecarboxylic acid in 200 mL DCM 0.6 g HOBt (0.11 eq.) and 7.45 g (1.1 eq.) EDC hydrochloride were added and the mixture was stirred vigorously at ambient temperature for 1.5 h. To the solution was added 40 mL methanol. The mixture was stirred overnight, extracted with water, and the organic phase dried over magnesium sulfate. The dry solution was filtered and concentrated in vacuum. The resulting residue was purified by chromatography (ethyl acetate/nTieptane 1 : 1), yielding 6.6 g of the title compound as colorless oil (yield 61%).To a 250 mL roundbottom flask containing a stir bar and 1- ((benzyloxy)carbonyl)piperidine-2-carboxylic acid (5.6 g, 20.0 mmol) was added DCM (100 mL). Stirring commenced and the following reagents were added in the order listed: TEA (4.2 mL, 3.0 g, 30.0 mmol), EDCI (4.20 g, 22.0 mmol), DMAP (0.248 g, 2.0 mmol), and 3- (3, 4, 5-trimethoxyphenyl)propan-l-ol (4.47 g, 19.8 mmol, dissolved in 10 mL DCM). The reaction mixture was sealed with a septa, flushed with nitrogen, and allowed to proceed overnight. The following day, the reaction mixture was transferred to a separatory funnel and extracted with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude product. This material was purified by silica gel chromatography (1 :3 ethyl acetate: hexanes, R/= 0.22) to yield the pure product as a clear oil (4.7 g, 50 %). ' H NMR (500 MHz) (CDCb) (amide rotamers) d: 7.35 - 7.25 (5H, m), 6.39 - 6.36 (2H, m), 5.15 - 5.10 (2H, m), 4.97 - 4.85 (1H, m), 4.17 - 4.04 (3H, m), 3.83 - 3.82 (9H, m), 3.10 - 2.94 (1H, app dt), 2.40 - 2.55 (2H, m), 1.98 - 1.88 (2H, m), 1.71 - 1.62 (3H, m), 1.47 - 1.39 (1H, m), 1.29 - 1.21 (1H, m). 13C NMR (125 MHz) (CDCb) (amide rotamers) d: 171.6, 153.1, 136.7, 136.5, 136.1, 128.4, 127.9, 127.7, 105.2, 67.3, 67.2, 64.2, 60.8, 56.0, 54.6, 54.4, 41.9, 32.4, 30.3, 26.7, 24.7, 24.5, 20.7, 20.6. HRMS calc'd for [M+Na] = 494.2155, observed = 494.2157. IR (NaCl, DCM): 2941, 1736, 1701, 1589, 1508, 1336, 1164, 1011, 981.

Molecular Weight:263.29
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:263.11575802
Monoisotopic Mass:263.11575802
Topological Polar Surface Area:66.8
Heavy Atom Count:19
Complexity:325
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes