92-13-7 Usage
Description
Pilocarpine acts by stimulating muscarinic receptors, therefore making it similar in action
to acetylcholine when systematically introduced. This compound differs from acetylcholine in that it does not react with any nicotinic receptors, but by stimulating the CNS.
Its effects are blocked by atropine. It has found therapeutic use in ophthalmology as a
myotic agent.
Chemical Properties
Colorless crystalline solid or an oil; melts at34°C (93.2°F); dissolves in water, alcohol,and chloroform; slightly soluble in ether andbenzene.
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 .
Uses
Pilocarpine occurs in the leaves of variousspecies of pilocarpus. It is used as an antidotefor atropine poisoning and in ophthalmologyto produce contraction of the pupil.
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
Clinical Use
Pilocarpine nitrate is mainly used to treat glaucoma clinically. Characterized with
the progressive cupping of the optic disk, hypopsia, and elevated intraocular pressure, the severe patients will go blind. Patients with angle-closure glaucoma (congestive glaucoma) generally have the narrow anterior chamber angle, the obstruction
of aqueous humor outflow, and the elevation of intraocular pressure, and these can
be reversed by a low-concentration pilocarpine. But it is noted that a highconcentration pilocarpine will promote the progress of glaucoma. Pilocarpine is
also used to treat open-angle glaucoma. The mechanism of the action is not entirely
clear. Using atropine and pilocarpine alternately prevents posterior synechiae. In
addition, pilocarpine is orally used to treat Zagari’s disease after neck radiotherapy,
increasing salivary secretion and sweat secretion
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).
References
Hardy., Bull. Soc. Chim. Fr., 24,497 (1875)
Gerrard., Pharm. J., 5,865,965 (1875)
Gerrard., ibid, 7,255 (1877)
Hardy, Calmels., Compt. rend., 102,1116,1251,1562 (1886)
Wagenaar., Pharm. Weekbl., 67, 285 (1930)
Preobrashenski et al., Ber., 63,460 (1930)
Preobrashenskietal., ibid, 69, 1835 (1936)
Roche, Lynch., Analyst, 73,311 (1948)
Pharmacology:
Hollander., Gastroenterology, 2, 20 I (1944)
Check Digit Verification of cas no
The CAS Registry Mumber 92-13-7 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 9 and 2 respectively; the second part has 2 digits, 1 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 92-13:
(4*9)+(3*2)+(2*1)+(1*3)=47
47 % 10 = 7
So 92-13-7 is a valid CAS Registry Number.
InChI:InChI=1S/C11H16N2O2/c1-3-10-8(6-15-11(10)14)4-9-5-12-7-13(9)2/h5,7-8,10H,3-4,6H2,1-2H3
92-13-7Relevant articles and documents
Syntheses of the racemic jaborandi alkaloids pilocarpine, isopilocarpine and pilosinine
Davies, Stephen G.,Roberts, Paul M.,Stephenson, Peter T.,Thomson, James E.
scheme or table, p. 3509 - 3512 (2009/09/30)
The synthesis of racemic pilocarpine has been achieved in high overall yield. Two alternative approaches for the formation of the γ-butyrolactone ring are described: the first involves a palladium-catalysed carbonylation reaction of a homopropargylic alco
A chemoenzymatic approach to (+)-pilocarpine
Csuk, René,Woeste, Barbara
, p. 9384 - 9387 (2008/12/22)
A short synthesis for the alkaloid (+)-pilocarpine has been developed. Key step of this synthesis is a chemoenzymatic resolution utilizing the lipase AP.
Synthesis of optically active lactones from L-aspartic acid and intermediates thereof
-
, (2008/06/13)
Optically active lactones are described, such as an intermediate lactone having the formula STR1 where R and R2 are each independently alkyl with 1 to 6 carbon atoms, cycloalkyl with 6 to 10 carbon atoms, aryl with 6 to 10 carbon atoms, or arylalkyl with 7 to 19 carbon atoms, R4 is H or C1-6 alkyl, and Ar is a homo- or heteroaromatic ring with 5 or 6 ring atoms being optionally substituted by C1-6 alkyl or alkoxy groups, halogen atoms, cyano or nitro groups. Such optically active, intermediate lactones are prepared from L-aspartic acid, and can be readily converted to (+)-pilocarpine and its analogues by hydrolysis, reduction, and hydrogenation, such as to an optically active lactone having the formula STR2 which is (+)-pilocarpine when R is ethyl, R4 is H, and Ar is 1-methylimidazol-5-yl.
