Loperamide synthesis
- Product Name:Loperamide
- CAS Number:53179-11-6
- Molecular formula:C29H33ClN2O2
- Molecular Weight:477.04
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].
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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.
References:
Wang, Min;Gao, Mingzhang;Zheng, Qi-Huang [Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,# 19,p. 5259 - 5263]
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