Loperamide hydrochloride synthesis

Yield:34552-83-5 67%

Reaction Conditions:

Stage #1: 4-(4-chlorophenyl)-4-hydroxypiperidinewith sodium carbonate;potassium iodide in 1,3-dioxolane-4-methanol; for 0.25 h;
Stage #2: N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide in 1,3-dioxolane-4-methanol at 60; for 2 h;
Stage #3: with hydrogenchloride in 1,3-dioxolane-4-methanol;isopropyl alcohol; for 0.333333 h;

Steps:

1

Example 1 : Preparation of 4-[4-(4-diphenyl)-4-hvdroxypiperidino1-N,N- dimethyl-2,2-diphenylbutyramide hydrochloride (loperamide)0.111 g (5.2-10-4 mol, 1 eq) of 4,4-chlorophenyl-4-hydroxypiperidine, 0.062 g (5.8-10-4 mol, 1.11 eq) of sodium carbonate, 0.0009 g (0.24% by weight) of potassium iodide were weighed and dissolved in 0.5 ml_ of glycerol formal. The resulting mixture was stirred for 15 minutes. Afterwards 0.2089 g (6.03-10-4 mol, 1.15 eq) of N,N-dimethyl-(3,3-diphenyltetrahydro-2- furyliden)ammonium bromide were added and heated at 6O⁰C. After 2 hours, the reaction mixture was left to cool to room temperature. The crude product was centrifuged at 18000 rpm for 30 minutes at 4O⁰C. The two phases were separated. To the supernatant 0.65 ml_ of isopropanol saturated with hydrochloric acid (7.8-10-4 mol of HCI, 1.5 eq) was added by stirring for 20 minutes. Then, 1 mL of H2O was added by stirring for 15 minutes. After this time, it was centrifuged at 9000 rpm for 1 hour at 21⁰C and the supernatant was removed. It was washed with water. The obtained solid was decanted and dried under vacuum. The title compound was obtained as a white solid. Yield: 67%. Rf (AcNH^Dioxane/MeOH; 20/40/40) =0.86. ¹H NMR (300 MHz,CDCI₃) δ 11.7 (1H, s, OH), 7.3-7.5 (14 H, m, Ar), 3 (1 H, s, CH₃), 2.36 (2H, t, CH₂, J=6 MHz), 2.25 (2H, t, CH₂, J=6 MHz), 14.94 (4H, t, J=6 MHz).

References:

WO2008/80601,2008,A2 Location in patent:Page/Page column 10