54143-57-6

Primperan,Delagrange,France,1964

Dopamine receptor antagonist; antiemetic.

ChEBI: A hydrate that is the monohydrate form of metoclopramide monohydrochloride.

Metoclopramide (Reglan) stimulates upper GI tract motility and has both central and peripheral actions. Centrally, it is a dopamine antagonist, an action that is important both for its often desirable antiemetic effect and other less desirable effects. Peripherally, it stimulates the release of intrinsic postganglionic stores of acetylcholine and sensitizes the gastric smooth muscle to muscarinic stimulation. The ability of metoclopramide to antagonize the inhibitory neurotransmitter effect of dopamine on the GI tract results in increased gastric contraction and enhanced gastric emptying and small bowel transit.

The N-(diethylaminoethyl)-2-methoxy-4-aminobenzamide used as the starting material may be prepared from o-toluidine. The o-toluidine is initially nitrated with nitric acid to produce 4-nitro-o-toluidine. The 4-nitro-o-toluidine is then converted to 2-hydroxy-4-nitrotoluene by heating with nitrous acid. By reacting the resulting 2-hydroxy-4-nitrotoluene with dimethyl sulfate, 2- methoxy-4-nitrotoluene is formed. The 2-methoxy-4-nitrotoluene is oxidized with potassium permanganate to produce 2-methoxy-4-nitrobenzoic acid. The latter substituted benzoic acid is treated with thionyl chloride to form 2- methoxy-4-nitrobenzoyl chloride. A methyl ethyl ketone solution of the 2- methoxy-4-nitrobenzoyl chloride is added over a period of about 1? hours to a methyl ethyl ketone solution containing an equal molecular quantity of N,Ndiethylethylene diamine while stirring and maintaining the temperature between 0°C and 5°C. The N-(diethylaminoethyl)-2-methoxy-4- nitrobenzamide hydrochloride formed precipitates. It is filtered, washed twice with methyl ethyl ketone, dissolved in alcohol, and reduced catalytically in an absolute isopropyl alcohol solution to form N-(diethylaminoethyl)-2-methoxy- 4-aminobenzamide. The base is obtained by precipitating with sodium hydroxide.
80 g (0.3mol) of N-(2-diethylaminoethyl)-2-methoxy-4-aminobenzamide are dissolved in small portions in 150 cc of acetic acid. The mixture is cooled and 45 g (0.45 mol) of acetic anhydride are added, and the solution obtained is heated for two hours on a water bath. After cooling, the solution is decanted into a round-bottomed flask with a stirrer, a thermometer and a tube for introducing the chlorine. It is stirred and the current of chlorine is passed through, the temperature being maintained between 20°C and 25°C. The stirring is continued for one hour after the completion of the absorption of the chlorine.
The mixture obtained is poured into 2 liters of water and the base is precipitated with 30% soda. The precipitated base is extracted with 400 cc of methylene chloride. After evaporation of the solvent, the N-(2- diethylaminoethyl)-2-methoxy-4-acetamino-5-chlorobenzamide formed crystallizes. The melting point is 86°C to 87°C and the yield is 95%.
To obtain the corresponding amino derivative, 109 g of base are heated under agitation in a round-bottomed flask with 300 cc of 35-36% concentrated hydrochloric acid and 600 cc of water. It is heated on a water bath until dissolution is complete, then maintained at boiling point for 90 minutes, cooled, diluted with 1 liter of water, and neutralized with about 350 cc of 30% soda. The N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide formed crystallizes, is centrifuged and washed in water. Its melting point is 122°C and the yield is 74%.
To obtain the corresponding dihydrochloride, the base is dissolved in absolute alcohol (3 volumes) and to that solution is added 5 N alcoholic hydrochloric acid. The dihydrochloride precipitates, is centrifuged and washed with alcohol. It is a solid white material, having a melting point of 134°C to 135°C.

Maxolon (King); Reglan (Baxter Healthcare); Reglan (Robins); Reglan (Schwarz Pharma).

Antiemetic

Metoclopramide is rapidly absorbed following an oral dose in a patient with intact gastric emptying. Peak plasma concentration is achieved within 40 to 120 minutes. With normal renal function, plasma half-life is about 4 hours.About 20% of an oral dose is eliminated unchanged in the urine, while 60% is eliminated as sulfate or glucuronide conjugates.

Improved gastric emptying will frequently alleviate symptoms in patients with diabetic, postoperative, or idiopathic gastroparesis. Since metoclopramide also can decrease the acid reflux into the esophagus that results from slowed gastric emptying or lower esophageal sphincter pressure, the drug can be used as an adjunct in the treatment of reflux esophagitis.

Side effects include fatigue, insomnia, and altered motor coordination. Parkinsonian side effects and acute dystonic reactions also have been reported. Metoclopramide stimulates prolactin secretion, which can cause galactorrhea and menstrual disorders. Extrapyramidal side effects seen following administration of the phenothiazines, thioxanthenes, and butyrophenones may be accentuated by metoclopramide.

Store at -20°C