92-13-7

Usage

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)

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

Upstream product

• 127-67-3 demethylmedicalpin 
• 74-88-4 methyl iodide 
• 92-13-7 isopilocarpine 
• 133868-53-8 (3S)-cis-3-ethyl-4-(3-methyl-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-dihydro-furan-2-one 
• 96914-10-2 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid ethyl ester 
• 96914-11-3 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid hexyl ester 
• 92598-80-6 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid butyl ester 
• 92598-82-8 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid benzyl ester 
• 92598-86-2 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid phenethyl ester 
• 92598-93-1 pilocarpic acid 4-methylbenzyl ester 
• 92598-81-7 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid 1-phenyl-ethyl ester 
• 92598-92-0 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid 2-methyl-benzyl ester 
• 92598-89-5 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid 4-chloro-benzyl ester 
• 92598-99-7 (2S,3R)-2-Ethyl-3-hydroxymethyl-4-(3-methyl-3H-imidazol-4-yl)-butyric acid 4-tert-butyl-benzyl ester 

Downstream Products

• 92-13-7 (+-)-isopilocarpine 
• 35672-00-5 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-1-(3-methyl-benzyl)-imidazolium; bromide 
• 55761-09-6 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-1-[2-hydroxyimino-2-(4-nitro-phenyl)-ethyl]-3-methyl-imidazolium; bromide 
• 59031-99-1 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-1-(2-hydroxyimino-2-phenyl-ethyl)-3-methyl-imidazolium; chloride 
• 59092-34-1 1-[2-(4-bromo-phenyl)-2-hydroxyimino-ethyl]-4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-imidazolium; chloride 
• 35835-37-1 1-benzyl-4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-imidazolium; bromide 
• 35671-98-8 1-(3,4-dichloro-benzyl)-4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-imidazolium; chloride 
• 35672-04-9 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-1-(4-nitro-benzyl)-imidazolium; chloride 
• 35672-09-4 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-1-[2-(4-nitro-phenyl)-2-oxo-ethyl]-imidazolium; bromide 
• 35671-97-7 1-(2,6-dichloro-benzyl)-4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-imidazolium; chloride 
• 35672-01-6 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-1-(4-methyl-benzyl)-imidazolium; bromide 
• 35835-36-0 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-1-phenethyl-imidazolium; bromide 
• 35672-05-0 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-1-(2-phenoxy-ethyl)-imidazolium; bromide 
• 35672-06-1 4-((3R)-4c-ethyl-5-oxo-tetrahydro-furan-3r-ylmethyl)-3-methyl-1-(3-phenoxy-propyl)-imidazolium; bromide 

Relevant academic research and scientific papers

Syntheses of the racemic jaborandi alkaloids pilocarpine, isopilocarpine and pilosinine

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 practical and scaleable total synthesis of the jaborandi alkaloid (+)-pilocarpine

The total synthesis of (+)-pilocarpine (as its nitrate salt) has been achieved in nine steps and 30% overall yield starting from racemic 2-(2′,2′-dimethoxyethyl)propane-1,3-diol, which was desymmetrised via an enzymatic protocol. A high yielding synthesis of a key α-ethylidene lactone precursor has been developed, which involves the palladium-catalysed decarboxylation/carbonylation of a 1,3-dioxan-2-one for formation of the γ-butyrolactone ring. Subsequent hydrogenation of the α-ethylidene lactone introduces the C(3)-stereochemistry to give a 72:28 mixture of (+)-pilocarpine and (+)-isopilocarpine, which are readily separable via recrystallisation of the (+)-pilocarpine nitrate salt.

A chemoenzymatic approach to (+)-pilocarpine

A short synthesis for the alkaloid (+)-pilocarpine has been developed. Key step of this synthesis is a chemoenzymatic resolution utilizing the lipase AP.

Convergent diastereoselective synthesis of isopilocarpine by one-pot Michael-addition-alkylation reaction

The metalated dithiane 7b available from imidazole aldehyde 6 is reacted with furanone 4 and ethyl iodide to give the lactone 8, which forms diastereoselectively. Its configuration is determined to be trans by means of a crystal structure analysis. The desulfurization of 8 leads to the alkaloid isopilocarpine 2 in three steps and 25% overall yield. The relative energies of the diastereomeric alkaloids 1 and 2 have been calculated.

Synthesis of optically active lactones from L-aspartic acid and intermediates thereof

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.

An Effective Chirospecific Synthesis of (+)-Pilocarpine from L-Aspartic Acid

A short and efficient synthesis of (+)-pilocarpine (1) has been accomplished in 10 steps and 51percent overall yield from L-aspartic acid.The synthesis features a diastereoselective alkylation of a protected aspartic acid diester derivative and a selective hydrolysis of the α-methyl ester to give the corresponding amino acid.Subsequent replacement of the amino group with bromo, esterification, and a modified Reformatsky reaction with 1-methylimidazole-5-carboxaldehyde (8) afforded imidazole-substituted lactone 28.Details concerning this novel lactone synthesis are also described.Finally, hydrogenolysis of the lactone carbon-oxygen bond and selective reduction of the resulting monoester afforded pure (+)-pilocarpine (1).

Process for preparing imidazole derivatives

Process for preparing imidazole derivatives of the general formula (II) : wherein R1 and R2 independently are loweralkyl, by desulfurizing a mercaptoimidazole derivative of the general formula (I) : wherein R1 and R2 are as defined above, with nitric acid optionally in the presence of a nitrite. The compounds of the formula (II) are useful for the treatment of glaucoma.

Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters

Various alkyl and aralkyl esters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the purpose of improving the ocular bioavailability of pilocarpine through increased corneal membrane permeability. The esters were found to undergo a quantitative cyclization to pilocarpine in aqueous solution of pH 3.5-10, the rate of cyclization being a function of the polar and steric effects within the alcohol portion of the esters. The rates of lactonization increased proportionally with the hydroxide ion activity over the pH range studied which is in accord with a reaction mechanism involving intramolecular nucleophilic attack of alkoxide ion on the ester carbonyl moiety. At pH 7.4 and 37° C, half-times of lactonization ranging from 30 min (p-chlorobenzyl ester) to 1105 min (n-hexyl ester) were observed for the various esters. The esters are markedly more lipophilic than pilocarpine. The results suggested that the pilocarpic acid esters may be potentially useful prodrugs, especially when further derivatized to give in vitro stable pilocarpic acid diesters.

Pilocarpine prodrugs II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters

Various novel diesters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the aim of improving the ocular delivery characteristics of the drug. The pilocarpic acid monoesters previously studied cyclized spontaneously to pilocarpine in aqueous solution and although they showed enhanced corneal permeability when compared with pilocarpine these monoesters suffered from poor solution stability. The present study shows that this problem can be totally overcome by blocking the free hydroxyl group in the monoesters. Diesters of pilocarpic acid were obtained by esterification of this group. Such compounds were found to possess a high stability in aqueous solution (shelf lives of more than 5 years at 20°C were estimated) but at the same time were readily converted to pilocarpine under conditions simulating those occurring in vivo through a sequential process involving enzymatic hydrolysis of the O-acyl bond followed by spontaneous lactonization of the intermediate pilocarpic acid monoester. Rate data are given for the conversion of the diesters in human plasma and in various rabbit eye homogenates. The pH-solubility profile was derived for a diester and lipophilicity parameters were determined for the compounds. All dieters were markedly more lipophilic than pilocarpine and the corresponding pilocarpic acid monoesters. The results suggest that pilocarpic acid diesters may be potentially useful pilocarpine prodrugs as they combine a high solution stability with an adequate rate of conversion to pilocarpine under in vivo conditions.