
53179-11-6
Name | Loperamide |
CAS | 53179-11-6 |
EINECS(EC#) | 258-416-5 |
Molecular Formula | C29H33ClN2O2 |
MDL Number | MFCD00600388 |
Molecular Weight | 477.04 |
MOL File | 53179-11-6.mol |
Synonyms
LOPERAMIDE
4-(4-chlorophenyl)-n,n-dimethyl-alpha,alpha-diphenyl-4-hydroxy-1-piperidineb
utanamide
4-[4-Chlorophenyl]-4-hydroxy-N, N-dimethyl-α,α-diphenyl-1-piperidinebutanamide
4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-N,N-dimethyl-2,2-diphenyl-butanamide
4-(4-Chlorophenyl)-4-hydroxy-N,N-dimethyl-,-diphenyl-1-p-piperidinebutanamide
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
Chemical Properties
Boiling point | 647.2±55.0 °C(Predicted) |
density | 1.187±0.06 g/cm3(Predicted) |
pka | pKa 8.66(H2O) (Uncertain) |
BCS Class | 4 |
LogP | 2.641 at 25℃ and pH6.95 |
CAS DataBase Reference | 53179-11-6(CAS DataBase Reference) |
NIST Chemistry Reference | Loperamide(53179-11-6) |
Hazard Information
Originator
Imodium,Janssen,UK,1975
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.
Manufacturing Process
23.6 parts of 2-oxo-3,3-diphenyl-tetrahydrofuranare melted at 100°C in an
oil-bath and gaseous hydrogen bromide is introduced into it during 3 hours.
The reaction mixture is cooled and triturated in benzene. The product is
filtered off, washed with petroleum ether and dried in an exsiccator, yielding
4-bromo-2,2-diphenylbutyric acid; MP 127.5%.
To a stirred suspension of 16 parts of 4-bromo-2,2-diphenylbutyric acid in 150 parts of chloroform are added dropwise 16 parts of thionyl chloride and the whole is stirred and refluxed for 2 hours. The reaction mixture is evaporated,yielding 4-bromo-2,2-diphenyl-butyrylchloride as a residue.
60 parts of 4-bromo-2,2-diphenylbutyrylchloride are dissolved in 400 parts of toluene and gaseous dimethylamine is introduced slowly into the solution while cooling (temperature is kept at about 0°C). The introduction is ceased when dimethylamine escapes from the cooler, and stirring is continued for 2 hours at ordinary temperature. The precipitated product is filtered off and dissolved in a minimum quantity of water. The product is extracted with chloroform. The extract is dried and evaporated. The residue solidifies on triturating in 4-methyl-2-pentanone. The solid is filtered off and dried, yielding dimethyl -(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide; MP 169° to 171.5°C.
A mixture of 6.33 parts of 4-(p-chlorophenyl)-4-piperidinol, 8 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2- pentanone is distilled azeotropically. Then there are added 12.12 parts of dimethyl-(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (from the preceding step) and the whole is stirred and refluxed for about 15 hours. The reaction mixture is filtered hot and the filtrate is evaporated.
The oily residue is dissolved in 2-propanol and to this solution is added an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The whole is evaporated and the oily residue is warmed in diluted hydrochloric acid solution. Upon the addition of toluene, the salt is precipitated. It is filtered off, boiled in acetone, and filtered off again after cooling, yielding 4- (p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenylpiperidine-1-butyramide hydrochloride; MP 222.1°C.
To a stirred suspension of 16 parts of 4-bromo-2,2-diphenylbutyric acid in 150 parts of chloroform are added dropwise 16 parts of thionyl chloride and the whole is stirred and refluxed for 2 hours. The reaction mixture is evaporated,yielding 4-bromo-2,2-diphenyl-butyrylchloride as a residue.
60 parts of 4-bromo-2,2-diphenylbutyrylchloride are dissolved in 400 parts of toluene and gaseous dimethylamine is introduced slowly into the solution while cooling (temperature is kept at about 0°C). The introduction is ceased when dimethylamine escapes from the cooler, and stirring is continued for 2 hours at ordinary temperature. The precipitated product is filtered off and dissolved in a minimum quantity of water. The product is extracted with chloroform. The extract is dried and evaporated. The residue solidifies on triturating in 4-methyl-2-pentanone. The solid is filtered off and dried, yielding dimethyl -(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide; MP 169° to 171.5°C.
A mixture of 6.33 parts of 4-(p-chlorophenyl)-4-piperidinol, 8 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2- pentanone is distilled azeotropically. Then there are added 12.12 parts of dimethyl-(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (from the preceding step) and the whole is stirred and refluxed for about 15 hours. The reaction mixture is filtered hot and the filtrate is evaporated.
The oily residue is dissolved in 2-propanol and to this solution is added an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The whole is evaporated and the oily residue is warmed in diluted hydrochloric acid solution. Upon the addition of toluene, the salt is precipitated. It is filtered off, boiled in acetone, and filtered off again after cooling, yielding 4- (p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenylpiperidine-1-butyramide hydrochloride; MP 222.1°C.
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.
Clinical Use
Loperamide is a synthetic
opioid subjected to extensive first-pass
metabolization after oral administration. Therefore
little intact drug reaches the systemic circulation
and the central nervous system. Loperamide
has no centrally mediated analgesic efficacy,
but may have a clinically useful analgesic effect via peripheral opioid receptors . Systemic
and central opioid side effects are widely
missing. Orally administered loperamide acts locally
in the gut by inhibition of intestinal motility
and secretion . Besides the strong μ-
opioid action, calcium and calmoduline antagonism
are involved in the antidiarrheal activity.
The compound is used in doses of 4–8 mg
for the treatment of acute and chronic diarrhea
and for the management of colostomies and
ileostomies . Adverse effects include nausea,
dry mouth, dizziness. High doses can induce
toxic megacolon and paralytic ileus. The compound
has no abuse and dependence potential
and is meanwhile available as over the counter
(OTC) product .
Synthesis
Loperamide, 1-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-|á,|á-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-(|?-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¨C36].
The starting 1-benzylpiperidin-4-one (3.1.48) is synthesized by Dieckmann intermolecular condensation of N-benzyl-N,N-bis-(|?-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¨C36].
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.
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