Physostigmine

Base Information

• Chemical Name: Physostigmine
• CAS No.: 57-47-6
• Deprecated CAS: 50975-37-6,511-49-9,511-49-9
• Molecular Formula: C15H21 N3 O2
• Molecular Weight: 275.351
• European Community (EC) Number: 200-332-8
• NSC Number: 30782
• UN Number: 2811,2757
• UNII: 9U1VM840SP
• DSSTox Substance ID: DTXSID3023471
• Nikkaji Number: J4.579I
• Wikipedia: Physostigmine
• Wikidata: Q410595
• NCI Thesaurus Code: C81337
• RXCUI: 8299
• Pharos Ligand ID: W2UV4MXDP5AB
• Metabolomics Workbench ID: 43233
• ChEMBL ID: CHEMBL94
• Mol file: 57-47-6.mol

Synonyms:Eserine;Physostigmine

Chemical Property of Physostigmine

Chemical Property:

• Appearance/Colour: solid
• Vapor Pressure: 2.12E-06mmHg at 25°C
• Melting Point: 102-104 °C(lit.)
• Refractive Index: 1.5600 (estimate)
• Boiling Point: 393.5°Cat760mmHg
• PKA: 6.12, 12.24(at 25℃)
• Flash Point: 191.8°C
• PSA: 44.81000
• Density: 1.166g/cm³
• LogP: 2.16770
• Storage Temp.: 2-8°C
• Sensitive.: Air & Light Sensitive
• Water Solubility.: Soluble in water (1:75), alcohol (1:10), chloroform (1:1), ether (1:30), and DMSO.
• XLogP3: 0.7
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 4
• Rotatable Bond Count: 2
• Exact Mass: 275.16337692
• Heavy Atom Count: 20
• Complexity: 403
• Transport DOT Label: Poison

Purity/Quality:

Physostigmine ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Toxic by ingestion.
• Hazard Codes: T+
• Statements: 26/28
• Safety Statements: 23-45-25

MSDS Files:

SDS file from LookChem

Total 1 MSDS from other Authors

Useful:

• Canonical SMILES: CC12CCN(C1N(C3=C2C=C(C=C3)OC(=O)NC)C)C
• Isomeric SMILES: C[C@@]12CCN([C@@H]1N(C3=C2C=C(C=C3)OC(=O)NC)C)C
• Recent ClinicalTrials: Acetylcholine, Tobacco Smoking, Genes and Nicotinic Receptors
• Recent EU Clinical Trials: Monocenter, double blind, randomised, placebo controlled study t evaluate Physostigmin for the Treatment of delirium in perioperative intensive care medicine
• Description: The classic AChEI, physostigmine, is an alkaloid obtained from seeds of the Calabar bean (Physostigma venenosum). Its parasympathomimetic effects were recognized long before its structure was elucidated in 1923. In 1929, Stedman found that the mechanism of the parasympathomimetic effects of physostigmine was inhibition of AChE; it inhibits AChE by acting as a substrate and carbamylating the enzyme. Acetylcholinesterase is carbamylated at a slow rate, but physostigmine has exceptionally high affinity (Ki ~ 10-9 M) for the catalytic site of the enzyme. By comparison, the Ks for acetylcholine is on the order of 10-4 M. Thus, physostigmine is classified as a reversible AChEI that carbamylates the enzyme at a slow rate; the carbamylated AChE also is regenerated quite slowly. Because physostigmine is a tertiary amine with a pKa of 8.2 (+BH) rather than a quaternary ammonium salt, it is more lipophilic than many other AChEIs and can diffuse across the blood-brain barrier. The tertiary amine also imparts pH dependence to its ability to inhibit AChE, because its affinity for AChE is greater when the amine is protonated.
• Physical properties: Appearance: flaky crystal. Solubility: slightly soluble in water; soluble in ethanol, benzene, and fatty oil. Melting point: 102–104 °C. Specific optical rotation: ?120° in benzene and ?76° in chloroform, respectively
• Uses: Physostigmine base (Eserine-Base) is used as bulk pharmaceuticals (parasympathomimetic, cholinergic, ophthalmic, anti-Alzheimer). Product Data Sheet It is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor obtained from the Calabar bean, used to treat glaucoma and delayed gastric emptying.
• Clinical Use: Physostigmine was used first as a topical application inthe treatment of glaucoma. Its lipid solubility properties permitadequate absorption from ointment bases. It is used systemicallyas an antidote for atropine poisoning and otheranticholinergic drugs by increasing the duration of actionof ACh at cholinergic sites through inhibition of AChE.Physostigmine, along with other cholinomimetic drugs actingin the CNS, has been studied for use in the treatment ofAlzheimer disease. Cholinomimetics that are currentlyused or which have been recently evaluated in the treatmentof Alzheimer disease include donepezil, galantamine, metrifonate,rivastigmine, and tacrine. It is anticipated that thislist will continue to grow as the etiology of this disease becomesbetter understood.

Technology Process of Physostigmine

There total 53 articles about Physostigmine which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield:

methyl isocyanate (624-83-9) + eseroline (469-22-7) → Physostigmin (57-47-6)

Guidance literature:

With sodium hydride; In tetrahydrofuran;

DOI:10.1021/jo00021a006

Reference yield:

(Z)-2-Methyl-4-triisopropylsilanyloxy-but-2-enoic acid (153109-50-3) → Physostigmin (57-47-6)

Guidance literature:

Multi-step reaction with 6 steps

1: 55 percent / DCC, HOBT / tetrahydrofuran / Heating

2: 94 percent / Pd₂(dba)3*CHCl₃, (S)-BINAP, 1,2,2,6,6-pentamethylpiperidine / N,N-dimethyl-acetamide / 1.5 h / 100 °C

3: 80 percent / 3M aq. HCl / tetrahydrofuran / Ambient temperature

4: 1.) Et₃N, MgSO₄, 2.) LiAlH₄ / 1.) THF, RT, overnight, 2.) THF, reflux, 1.5 h

5: BBr₃ / CH₂Cl₂ / 23 °C

6: NaH / diethyl ether

With 1,2,2,6,6-pentamethylpiperidine; hydrogenchloride; tris(dibenzylideneacetone)dipalladium⁽⁰⁾ chloroform complex; lithium aluminium tetrahydride; boron tribromide; sodium hydride; magnesium sulfate; benzotriazol-1-ol; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); triethylamine; dicyclohexyl-carbodiimide; In tetrahydrofuran; diethyl ether; dichloromethane; N,N-dimethyl acetamide;

DOI:10.1021/ja980788+

Reference yield:

(Z)-2-Methyl-4-triisopropylsilanyloxy-but-2-enoic acid (2-iodo-4-methoxy-phenyl)-methyl-amide (153109-51-4) → Physostigmin (57-47-6)

Guidance literature:

Multi-step reaction with 5 steps

1: 94 percent / Pd₂(dba)3*CHCl₃, (S)-BINAP, 1,2,2,6,6-pentamethylpiperidine / N,N-dimethyl-acetamide / 1.5 h / 100 °C

2: 80 percent / 3M aq. HCl / tetrahydrofuran / Ambient temperature

3: 1.) Et₃N, MgSO₄, 2.) LiAlH₄ / 1.) THF, RT, overnight, 2.) THF, reflux, 1.5 h

4: BBr₃ / CH₂Cl₂ / 23 °C

5: NaH / diethyl ether

With 1,2,2,6,6-pentamethylpiperidine; hydrogenchloride; tris(dibenzylideneacetone)dipalladium⁽⁰⁾ chloroform complex; lithium aluminium tetrahydride; boron tribromide; sodium hydride; magnesium sulfate; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); triethylamine; In tetrahydrofuran; diethyl ether; dichloromethane; N,N-dimethyl acetamide;

DOI:10.1021/ja980788+

upstream raw materials:

formaldehyd

(-)-N¹-norphysostigmine fumarate

methyl isocyanate

eseroline

Downstream raw materials:

Ethyl N-methylcarbamate

methylammonium carbonate

methylamine

N-Methylurea

Refernces

• 1、 Yi, Wei,Fang, Xing-Xiao,Liu, Qing-Yun,Liu, Gong-Qing. "Metal-Free Synthesis of Oxazolidine-2,4-diones and 3,3-Disubstituted Oxindoles via ICl-Induced Cyclization". . p. 6671 - 6681. Retrieved 2019/01/04.
• 2、 Pinto, Artur,Jia, Yanxing,Neuville, Luc,Zhu, Jieping. "Palladium-catalyzed enantioselective domino heck-cyanation sequence: Development and application to the total synthesis of esermethole and physostigmine". . p. 961 - 967. Retrieved 2007/10/03.