Pethidine EP Impurity A HCl synthesis

Yield:10272-50-1 77%

Reaction Conditions:

Stage #1: formaldehyd;4-phenylpiperidine hydrochloridewith sodium tris(acetoxy)borohydride;acetic acid in dichloromethane;water at 20; for 24 h;
Stage #2: with sodium hydrogencarbonate in dichloromethane;water;
Stage #3: with hydrogenchloride in diethyl ether;dichloromethane;

Steps:

10.A

Example 10: (E)-N-Hydroxy-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-yI)-phenyl]-3- oxo-propenyl}-phenyl)-acrylamde; STEP A; A mixture of 4-phenyl piperidine hydrochloride (1.23 g, 6.2 mmol), formaldehyde (36.5% in H₂O, 0.702 ml, 9.3 mmol), NaBH(OAc)₃ (2.63 g, 12.42 mmol) and AcOH (0.71 ml, 12.42 mmol) in DCM (30 ml) was stirred for 24 hours at room temperature. The mixture was then brought to basic conditions with a 5% NaHCO₃ solution and extracted twice with DCM. The pooled organic phases were dried over Na₂SO₄ and evaporated to dryness. The residue was dissolved in DCM and treated with HCI in Et₂O observing the precipitation of a white solid. The solid was filtered off through a Buchner funnel to obtain 1 g of 1-methyl-4- phenylpiperidine hydrochloride as a white solid. Y = 77%

References:

WO2007/113249,2007,A2 Location in patent:Page/Page column 41