53179-11-6

Basic information

• Product Name: Loperamide
• Synonyms: 4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide;Tebloc;4-(4-Chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutyramide;4-[4-(p-Chlorophenyl)-4-hydroxypiperidino]-2,2-diphenyl-N,N-dimethylbutyramide;4-[4-Hydroxy-4-(4-chlorophenyl)-1-piperidinyl]-2,2-diphenyl-N,N-dimethylbutanamide;C07080;4-(4-CHLOROPHENYL)-4-HYDROXY-N,N DIMETHYL-A,A DIPHENYL-1-PEIPERIDINE BUTANAMIDEHCL;4-(4-chlorophenyl)-n,n-dimethyl-alpha,alpha-diphenyl-4-hydroxy-1-piperidineb
• CAS NO: 53179-11-6
• Molecular Formula: C₂₉H₃₃ClN₂O₂
• Molecular Weight: 477.04
• EINECS: 258-416-5
• Mol File: 53179-11-6.mol

Chemical Properties

• Boiling Point: 647.2 °C at 760 mmHg
• Flash Point: 345.2 °C
• Appearance: /
• Density: 1.187g/cm³
• Vapor Pressure: 1.23E-17mmHg at 25°C
• Refractive Index: 1.6
• PKA: pKa 8.66(H2O) (Uncertain)
• CAS DataBase Reference: Loperamide(CAS DataBase Reference)
• NIST Chemistry Reference: Loperamide(53179-11-6)
• EPA Substance Registry System: Loperamide(53179-11-6)

Safety Data

• Hazardous Substances Data: 53179-11-6(Hazardous Substances Data)

Usage

Uses

Loperamide is presently used more often as an antidiarrheal drug than as an analgesic, and it is also included in the list of over-the-counter drugs because of its insignificant action on the CNS. It reduces intestinal smooth muscle tone and motility as a result of binding to intestinal opiate receptors. It is used for symptomatic treatment of severe and chronic diarrhea of various origins. The most popular synonym for loperamide is imodium.

Definition

ChEBI: A synthetic piperidine derivative, effective against diarrhoea resulting from gastroenteritis or inflammatory bowel disease.

Brand name

Ami-29;Colifelin;Colifilm;Diareze;Dissenter;Duplibiot;Elcoman;Firtasec;Loperan;Loperin;Lopermid;Motilix;Orulop;Pf 185;Pricilone;R-18553;Regulane;Seldiar;Taguinol;Telboc;Totrtasec.

Therapeutic Function

Antidiarrheal

World Health Organization (WHO)

Loperamide, an inhibitor of intestinal peristalsis, was introduced in 1975 for the treatment of acute and chronic diarrhoea. In many countries its use was discouraged in young children. In late 1989, treatment of infants in Pakistan was associated with 19 cases of paralytic ileus, 6 of which have been fatal. This has subsequently led the major manufacturer to withdraw all drop formulations of the drug worldwide as well as the lower dose syrup forms from countries where there is a programme for the control of diarrhoeal diseases. The WHO Control of Diarrhoeal Diseases Programme recommends that loperamide should not be used in children below five year of age. (Reference: (LJJ) Letter to WHO from Johnson & Johnson, , , 21 June 1990)

General Description

Loperamide (Imodium) is a 4-phenylypiperidine with amethadone-like structure attached to the piperidine nitrogen. It acts as an antidiarrheal by directly binding tothe opiate receptors in the gut wall. Loperamide inhibitsacetylcholine and prostaglandin release, decreasing peristalsisand fluid secretion thus increasing the GI transit time andreducing the volume of fecal matter.Loperamide is sufficiently lipophilic to cross the blood-brain barrier, yet itdisplays no CNS-opioid effects. The reason for this is that itis actively pumped out of the brain via the P-glycoproteinpump (MDR1). Knockout mice with the P-glycoproteinpump genetically removed were given radiolabeled loperamideand sacrificed 4 hours later. The [3H]loperamideconcentrations were measured and compared with wild-typemice. A 13.5-fold increase in loperamide concentration wasfound in the brain of the knockouts. In addition, the micelacking the P-glycoprotein pump displayed pronouncedsigns of central opiate agonism. Loperamide is availableas 2-mg capsules for treatment of acute and chronic diarrhea.Recommended dosage is 4 mg initially, with 2 mgafter each loose stool for a maximum of 16 mg/d.

Synthesis

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].

Veterinary Drugs and Treatments

Loperamide is used as a GI motility modifier in small animals. Use in cats is controversial and many clinicians do not recommend using in cats.

InChI:InChI=1/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3

Synthetic route

loperamide N-oxide → loperamide (53179-11-6)

Conditions	Yield
With sodium tetrahydroborate In ethanol; water at 50 - 60℃; chemoselective reaction;	95%

4-(4-chlorophenyl)-4-hydroxypiperidine (39512-49-7) + N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide (37743-18-3) → loperamide (53179-11-6)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 80℃;	80%
With sodium carbonate; 4-methyl-2-pentanone at 80℃; Dean-Stark; Reflux;	38%

4-Bromo-2,2-diphenylbutyric acid (37742-98-6) → loperamide (53179-11-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: thionyl chloride; dimethylformamide / CHCl3 / 4 h / Heating 2: Na2CO3 / tetrahydrofuran 3: 80 percent / Na2CO3 / dimethylformamide / 80 °C View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / chloroform / 4 h / Reflux 2: sodium carbonate / water; toluene / 0 - 20 °C 3: 4-methyl-2-pentanone; sodium carbonate / 80 °C / Dean-Stark; Reflux View Scheme

4-bromo-2,2-diphenylbutyric acid chloride (50650-44-7) → loperamide (53179-11-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: Na2CO3 / tetrahydrofuran 2: 80 percent / Na2CO3 / dimethylformamide / 80 °C View Scheme
Multi-step reaction with 2 steps 1: sodium carbonate / water; toluene / 0 - 20 °C 2: 4-methyl-2-pentanone; sodium carbonate / 80 °C / Dean-Stark; Reflux View Scheme

3,3-Diphenyl-dihydro-furan-2-one (956-89-8) → loperamide (53179-11-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen bromide; acetic acid / 48 h / 20 °C 2: thionyl chloride / chloroform / 4 h / Reflux 3: sodium carbonate / water; toluene / 0 - 20 °C 4: 4-methyl-2-pentanone; sodium carbonate / 80 °C / Dean-Stark; Reflux View Scheme

loperamide (53179-11-6) → loperamide N-oxide

Conditions	Yield
With dihydrogen peroxide In methanol for 168h;

Upstream product

• 39512-49-7 4-(4-chlorophenyl)-4-hydroxypiperidine 
• 37743-18-3 N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide 
• 956-89-8 3,3-Diphenyl-dihydro-furan-2-one 
• 50650-44-7 4-bromo-2,2-diphenylbutyric acid chloride 
• 37742-98-6 4-Bromo-2,2-diphenylbutyric acid 

Relevant articles and documents

A high-yield route to synthesize the P-glycoprotein radioligand [ 11C]N-desmethyl-loperamide and its parent radioligand [ 11C]loperamide

N-Desmethyl-loperamide and loperamide were synthesized from α,α-diphenyl-γ-butyrolactone and 4-(4-chlorophenyl)-4- hydroxypiperidine in five and four steps with 8% and 16% overall yield, respectively. The amide precursor was synthesized from 4-bromo-2,2- diphenylbutyronitrile and 4-(4-chlorophenyl)-4-hydroxypiperidine in 2 steps with 21-57% overall yield. [11C]N-Desmethyl-loperamide and [ 11C]loperamide were prepared from their corresponding amide precursor and N-desmethyl-loperamide with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 20-30% and 10-15% radiochemical yields, respectively, based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.

Solid Pharmaceutical Preparations Containing Copolymers Based On Polyethers Combined With Poorly Water-Soluble Polymers

The invention relates to dosage forms which contain preparations of poorly water-soluble substances in a polymer matrix of polyether copolymers, said polyether copolymers being obtained by the radically initiated polymerization of a mixture from 30 to 80% by weight of N-vinyl lactam, 10 to 50% by weight of vinyl acetate and 10 to 50% by weight of a polyether, and at least one poorly water-soluble polymer, the poorly water-soluble substance being present in the polymer matrix as an amorphous substance.

A chemoselective deoxygenation of N-oxides by sodium borohydride-Raney nickel in water

A simple and convenient protocol for deoxygenation of aliphatic and aromatic N-oxides to the corresponding amines in good to excellent yield using sodium borohydride-Raney nickel in water is reported. Other functional moieties such as alkenes, halides, ethers, and amides are unaffected under the present reaction condition.

Floating pharmaceutical composition comprising an active phase and a non-active phase

The invention concerns a floating pharmaceutical composition consisting of at least a first phase comprising at least a high dose active principle combined with one or several carriers and at least a second phase comprising at least a gas-generating system. The invention also concerns tablets comprising such a pharmaceutical composition and a method for preparing such tablets.

Design and synthesis of 4-phenyl piperidine compounds targeting the mu receptor

Small molecule mu agonists based on the 4-phenyl piperidine scaffold were designed and synthesized to further investigate the therapeutic potential of loperamide analogs. The resulting compounds show excellent agonistic activity towards the human mu receptor with interesting SAR trends within the series. Small molecule mu agonists based on the 4-phenyl piperidine scaffold were designed and synthesized to further investigate the therapeutic potential of loperamide analogs. The resulting compounds show excellent agonistic activity towards the human mu receptor with interesting SAR trends within the series.

Method for treating gastrointestinal distress

This invention relates to a pharmaceutical composition for treating gastrointestinal distress comprising an effective amount of an antidiarrheal composition, e.g. loperamide, and an antiflatulent effective amount of simethicone and methods of treating gastrointestinal distress comprising administering such pharmaceutical compositions.

Loperamide (R 18 553), a novel type of antidiarrheal agent. V. The pharmacokinetics of loperamide in rats and man

Tritium labelled loperamide was administered in a dose of 2.0 mg to 3 normal men, and of 1.25 mg/kg to rats. Urine and feces were collected up to 8 days for the men, and up to 4 days for the rats. Blood samples were taken at regular intervals in the men; groups of rats were killed at different times after drug administration in order to examine blood, organs and tissues. In one rat the bile was drained for 48 hr. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. The fate of orally administered loperamide 3H appeared to be similar in rats and in man. Only 5 to 10% of the drug and its metabolites was recovered from the urine, the bulk being excreted with the feces. Plasma and tissue levels were low at all times. The existence of an enterohepatic shunt was shown, but uptake of the drug into the general circulation was low.