4-Piperidinamine, 1-(phenylmethyl)-, hydrochloride (1:2)

REFERENCE EXAMPLE 4 1-Benzyl-4-[N-(o-nitrobenzyl)-amino]-piperidine dihydrochloride STR108 In this reference example, 5.24 g of REFERENCE 1-Benzyl-4-[N-(o-nitrobenzyl)-amino]-piperidine dihydrochloride STR72 In this reference example, 5.24 g of Preparation 8 Preparation of 4-n-Butyramidopiperidine hydrochloride 4-Amino-1-benzylpiperidine dihydrochloride (7.4 g) in dry chloroform (75 ml) was cooled to 0-10 and treated dropwise with triethylamine (16.6 ml). n-Butyric anhydride (4.7 g) was added slowly to the cooled solution, then the mixture was kept at 0-5 for 15 minutes and at room temperature for 1 hour. Water (80 ml) was added and the chloroform phase separated, washed with 10% aqueous sodium hydroxide (50 ml) then with water (50 ml), dried (MgSO4) and evaporated in vacuo to give crude crystalline 4-n-butyramido-1-benzylpiperidine (6.5 g). This was dissolved in ethanol (65 ml) containing 2 N hydrochloric acid (5 ml) and hydrogenated over a palladium on charcoal catalyst at 50/50 p.s.i. until uptake of hydrogen ceased. The catalyst was removed by filtration and the ethanol was removed by distillation in vacuo. The residue was re-dissolved in water (60 ml) and extracted with chloroform (3*50 ml). The aqueous phase was treated with acetic acid to pH 3 and evaporated in vacuo. The residue was dissolved in ethanol (60 ml), filtered and re-evaporated in vacuo to give a colorless oil which solidified. After trituration with ether (100 ml), crude deliquescent 4-n-butyramidopiperidine hydrochloride (m.p. 141-3) (4.2 g) was recovered by filtration.A solution of (i?)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalyl chloride(86 mL, 1.0 mol) in 100 mL CH2CI2 were refluxed for 2 hours in a flask equipped with a CaCl2 guard tube. After the solution was cooled to room temperature the solvents and excess oxalyl chloride were removed by evaporation under reduced pressure. The resulting acid chloride was dissolved in 200 mL CH2CI2 and added dropwise to a solution of 1 -benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) and triethylamine (240 mL, 1.7 mol) in 300 mL CH2C12 cooled in an ice bath. The resulting mixture was stirred for 2 hours at room temperature and subsequently washed twice with 300 mL portions of 5% aq. NaHC03 and 300 mL saturated aq. NaCl solution, dried over Na2S04, filtered, and evaporated to dryness under reduced pressure. The solid residue was triturated with 500 mL heptanes, collected by filtration, and washed twice with 200 mL portions of heptanes. The solid was air-dried at 45 C to yield (i?)-tetrahydrofuran-2-carboxylic acid (l-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid. ^-NMR (300 MHz, CDCI3): 8 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd, J= 5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H), 2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m, 2H) ppm.

Molecular Weight:226.74
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:226.1236763
Monoisotopic Mass:226.1236763
Topological Polar Surface Area:29.3
Heavy Atom Count:15
Complexity:156
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes