PILOCARPINE

Physical properties

Appearance: colorless crystal or white crystalline powder. Solubility: freely soluble in water; slightly soluble in ethanol; insoluble in chloroform or diethyl ether. Melting point: 174–178?°C.

History

It has a history of hundreds of years since pilocarpine was used to treat glaucoma .In 1933, the chemical synthesis of pilocarpine was firstly reported. However, pilocarpine couldn’t be used for treatments, because its synthetic route is so long and focuses on isopilocarpine, of which the pharmacological activities are 1/20– 1/50 of pilocarpine. In 1972, DeGraw successfully synthesized the cis-homopilopic acid employing catalytic hydrogenation of precious metals and obtained pilocarpine as the main part product. Therefore, the study on the production of pilocarpine by chemical synthesis has made new progress and has been artificially synthesized .

Definition

ChEBI: The (+)-enantiomer of pilocarpine.

Health Hazard

Pilocarpine is a tropane alkaloid. Toxicsymptoms are characterized by muscariniceffects. Toxic effects include hypersecretionof saliva, sweat, and tears; contraction of thepupils of the eyes; and gastric pain accom panied with nausea, vomiting, and diarrhea.Other symptoms are excitability, twitching,and lowering of blood pressure. High dosesmay lead to death due to respiratory failure.A lethal dose in humans is estimated withinthe range of 150–200 mg.

Pharmacology

Pilocarpine activates cholinergic M-receptor and has an obvious effect on eyes and salivary glands. Pilocarpine nitrate eye drops take part in the actions of myosis, depressing intraocular pressure and alleviating cyclospasm. It increases glandular secretions at 10–20? mg, i.h., including the sweat gland, salivary gland, lacrimal gland, gastric gland, pancreas, intestinal gland, respiratory mucosa, and so on. Pilocarpine activates intestinal smooth muscle and promotes its tension and peristalsis. It induces asthma by activating bronchial smooth muscle and activates smooth muscles of uterus, bladder, gallbladder, and biliary passage as well

Safety Profile

A human poison by subcutaneous route. Poison experimentally by ingestion, intravenous, intraperitoneal, and subcutaneous routes. A very poisonous alkaloid that is used to remove excess fluid accumulations from the body. Its action on the sweat glands makes it a powerful sudorific. It very rarely causes death, but, when it does, it is by paralysis of the heart or edema of the lungs. Dangerous; on heating to decomposition it emits toxic fumes of NOx.

Synthesis

Pilocarpine, 3-ethyl-4-(1-methyl-5-imidazolymethyl)tetrahydrofuran-2-one (13.1.22), is an alkaloid that is made from leaves of the tropic plant Pilocarpus jaborandi. It is synthesized in a few different ways [25–32], the most relevant of which seems to be from 2-ethyl-3-carboxy-2-butyrolactone [25–27], which with the help of thionyl chloride is turned into the acid chloride (13.1.15) and further reacted with diazomethane and ethanol, to give the corresponding ethyl ester (Arndt–Eistert reaction), which is hydrolyzed into the acid (13.1.16). The resulting acid (13.1.16) is again changed into the acid chloride (13.1.17) by thionyl chloride. The obtained acid chloride is treated with diazomethane. But in this case the intermediate forming ketene is treated with hydrogen chloride to give the chloroketone (13.1.18). Reacting this with potassium phthalimide and subsequent removal of the phthalimide protecting group by acid hydrolysis gives the aminoketone (13.1.19), which is reacted with an acidic solution of potassium thiocyanate, forming 3-ethyl-4-(2- mercapto-5-imidazolylmethyl)tetrahydrofuran-2-one (13.1.20). Mild oxidation of this product allows to remove the mercapto- group from the product (13.1.20), giving 3-ethyl- 4-(5-imidazolylmethyl)tetrahydrofuran-2-one (13.1.21). Alkylation of the resulting product with methyl iodide leads to the formation of pilocarpine (13.1.22).