ChemicalBook CAS DataBase List Loperamide

Loperamide synthesis

4synthesis methods

Product Name:Loperamide
CAS Number:53179-11-6
Molecular formula:C29H33ClN2O2
Molecular Weight:477.04

Loperamide, 1-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1- piperidinebutyramide (3.1.55), proposed here as an analgesic, is synthesized by the alkylation of 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) using N,N-dimethyl(3,3- diphenyltetrahydro-2-furylidene)ammonium bromide (3.1.54) in the presence of a base. The 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) is synthesized by reacting 1-benzylpiperidine-4-one (3.1.48) with 4-chlorophenylmagnesiumbromide, followed by debenzylation of the product (3.1.49) by hydrogenation using a palladium on carbon catalyst.

The starting 1-benzylpiperidin-4-one (3.1.48) is synthesized by Dieckmann intermolecular condensation of N-benzyl-N,N-bis-(β-carboethoxyethyl)amine (3.1.46), which is easily formed by reaction of benzylamine with ethyl acrylate to give 1-benzyl-3-carboethoxypiperidine-4-one (3.1.47) followed by acidic hydrolysis and thermal decarboxylation.
N,N-Dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54) is synthesized from diphenylacetic acid ethyl ester, which is reacted with ethylene oxide in the presence of sodium hydroxide, giving 2,2-diphenylbutyrolactone (3.1.51). Reacting this with hydrogen bromide in acetic acid opens the lactone ring, forming 2,2-diphenyl-4-bromobutyric acid (3.1.52). This transforms into acid chloride (3.1.53) using thionyl chloride, which cyclizes upon further treatment with an aqueous solution of dimethylamine, thus forming the desired N,N-dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54). Reacting this with 4-(4-chlorphenyl)-4-hydroxypiperidine (3.1.50) gives the desired loperamide (3.1.55) [34–36].

39512-49-7 Synthesis

39512-49-7
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3,3-Diphenyltetrahydrofuran-2-ylidene(dimethyl)ammonium bromide

37743-18-3
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53179-11-6
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Yield:53179-11-6 38%

Reaction Conditions:

with sodium carbonate;4-methyl-2-pentanone at 80;Dean-Stark;Reflux;

Steps:

4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-N,N-dimethyl-2,2-diphenylbutanamide(loperamide, 9).
A mixture of 4-(4-chlorophenyl)-4-hydroxypiperidine (123mg, 0.58mmol), Na₂CO₃ (231mg, 2.18mmol) in ⁱBuCOMe (18mL) was distilled azeotropically to dry with the aid of a Dean-Stark trap. After cooling to 80°C, compound 8 (200mg, 0.58mmol) was added. The reaction mixture was heated and refluxed overnight. The solvent was removed in vacuo. The residue was diluted with water, and extracted with CHCl₃. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was first purified by column chromatography with ammonium hydroxide solution (2M) in MeOH/CH₂Cl₂ (1:10). Then the product purified by silica gel column was injected onto onto a Luna C18 column (5μm, 100A, 10×250mm), and eluted at 5.0mL/min 40% solvent A (water/0.1% TFA) and 60% solvent B (acetonitrile/0.1% TFA) to afford compound 9 (126mg, 38%, TFA salt) as a white solid, mp 103-104°C. ¹H NMR (CDCl₃): δ 11.10 (s, 1H), 7.43-7.40 (m, 4H), 7.37-7.26 (m, 10H), 5.44 (s, 1H), 3.34 (d, J=10.0Hz, 2H), 3.20 (q, J=10.5Hz, 2H), 2.94 (s, 3H), 2.76-2.75 (m, 2H), 2.64-2.61 (m, 2H), 2.44-2.40 (m, 2H), 2.29 (s, 3H), 1.83 (d, J=14.5Hz, 2H). ¹³C NMR (CDCl₃): δ 144.7, 138.9 133.6, 129.2, 128.8, 128.0, 127.9, 126.1, 69.1, 60.2, 55.6, 49.2, 39.6, 39.4, 37.4, 35.6. LC-MS (ESI, m/z): Calcd for C₂₉H₃₄ClN₂O₂ ([M+H]⁺) 477.2, found: 477.2.