1-[(Benzyloxy)carbonyl]piperidine-4-carboxylic acid

Whtie powder

To a solution of isonipecotic acid (1.29g, 10 mmol) in a mixture of CH3CN/H2O (2:3, 0.1M), NaHCO3 (1.5eq) and Na2CO3 (1.5 eq) were added (pH~ 10-11). Once the mixture was cooled to 0 °C, Cbz-Cl (1.42 mL, 1.7 g, 10 mmol). was slowly added The resulting solution was stirred for 2 h at rt. After completion ofthe reaction, the mixture was acidified by dropwise addition of a 1 N HCl aqueous solution. Then, CH3CNwas removed by evaporation, followed by the extraction with EtOAc (3x). Finally the combined organicphase was washed with brine, dried over Na2SO4, and concentrated to afford the desired product inquantitative yield, which was used in the next reaction without further purification.Stage (i): Stage (i): To piperidine-4-carboxylic acid (25 g) in THF (75 ml) there was added water (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 h at room temperature (TLC monitoring). When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2.x.150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (NaWater (75 ml), followed by sodium bicarbonate (30.8 g), was added to piperidine-4-carboxylic acid (25 g) in THF (75 ml). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 h at room temperature (TLC monitoring). When the conversion was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2.x.150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (NaStep (i): Synthesis of the amine unit AMN-08: 9-Pyridin-4-yloxy)-3- azaspiro[5.5]undecane dihydrochloride (AMN-08); Stage (i): 1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid; Water (75 ml) was added to piperidine-4-carboxylic acid (25 g) in THF (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0 To a solution of piperidine-4-carboxylic acid in a 1:1 mixture Of HTo an aqueous solution (i.e., 300 ml of distilled water) of isonipecotic acid (10.0 g, 77.4 mmol) and sodium bicarbonate (19.5 g, 232 mmol) was added benzyl chloroformate (11.5 ml, 80.9 mmol). The reaction solution was stirred at room temperature for 20 hours, and ethyl acetate was added thereto then the solution was separated. Concentrated hydrochloric acid was added to the aqueous layer to bring a pH level to 1, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure to give a title compound (14.7 g, 55.8 mmol, 72percent) as a colorless oil product. (1) To a stirred solution of pipehdine-4-carboxylic acid (5.0 g, 38.7 mmol) and NaOH (1.86 g, 46.5 mmol) in HSTR76 Step A: N-CBZ-isonipecotic acid Example SA 2-[(PIPERIDINE-4-CARBONYL)-AMINO]-PROPIONIC acid tert-butyl ester A solution of isonipecotic acid (25 g, 194 mmol) in 3 N NaOH (130 mL) at 0°C was treated with CbzCl over 15 min with vigorous stirring. Then the reaction mixture was stirred at ambient temperature for 18 h and partitioned with diisopropyl ether (2x250 mL). The aqueous layer was separated, made acidic with 4 N HC1, and extracted with EtOAc (2x250 mL). The combined organic layers were dried (MGS04), filtered and concentrated under reduced pressure to provide piperidine-1, 4-dicarboxylic acid monobenzyl ester (40.2 g) as a clear colorless viscous oil. A portion of this material (26.5 g, 100 mmol) in THF (100 mL) was treated with DMF (5 drops) followed by dropwise addition of oxalyl chloride (8.67 mL, 100 mmol). When the evolution of gas had ceased the mixture was stirred for an additional 30 min and concentrated under reduced pressure. The residue obtained was evaporated from toluene (1X75 mL). The resulting acid chloride was dissolved in THF (220 mL) and treated with (L)-ALANINE-TERT-BUTYL ester HC1 salt (18.2 g, 100 mmol) and N, N-diisopropyl- ethylamine (52 mL, 300 mmol) at 0°C. The mixture was warmed to ambient temperature and stirred for two hours. To this DMAP (240 mg, 1.90 mmol) was added in one portion and the resulting white sus- pension was stirred for 65 h. The reaction mixture was quenched with 4 M HC1 and partitioned with EtOAc. The organic phase was separated, washed with a solution of aqueous NAHC03 followed by brine, dried (MGS04), filtered and concentrated under reduced pressure to provide 4- (L-TERT-BUTOXYCARBONYLETHYL- CARBAMOYL)-PIPERIDINE-L-CARBOXYLIC acid benzyl ester. This was subjected to hydrogenolysis next.;Example 11F PIPERIDINE-1, 4-DICARBOXYLIC acid monobenzyl ester A 2000 mL flask was charged with isonipecotic acid (100 g, 776 mmol) and 3 N NaOH (550 mL), and was cooled with an ice bath to 14°C (internal temperature). CbzCl (145 mL) was added dropwise and the temperature gradually rose to 25°C during the addition over 20 min. The mixture was vigorously stirred and the cooling bath removed. The mixture was stirred overnight and the next morning poured directly into a 2 L sep. funnel and extracted with diisopropyl ether (2XLOOOML). The aqueous layer was acidified with 4 N HC1, extracted with EtOAc (2X1000 mL), dried over MGSO4, filtered and concentrated affording 210 g of acid, as a clear colorless viscous oil which was crystallized upon cooling. This was dried to provide the title compound (208 g, 100percent). LH NMR (400 MHz, DMSO-d6) 10.67 (s, 1H), 7.42-7. 30 (m, 5H), 5.13 (s, 2H), 4.08-4. 02 (m, 2H), 3.10-2. 89 (m, 2H), 2.5 (m, 1H), 1.94-1. 89 (m, 2H), 1.621. 52 (m, 2H).To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) and Na

Molecular Weight:263.29
XLogP3:1.6
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:317
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes