51-60-5

Basic information

• Product Name: 3-[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium methyl sulfate
• Synonyms: A sulfuric acid neostigmine;(3-(dimethylcarbamoyloxy)phenyl)trimethyl-ammoniumethylsulfate;(3-hydroxyphenyl)trimethylammoniummethylsulfatedimethylcarbamicester;(m-hydroxyphenyl)trimethylammoniummethylsulfatedimethylcarbamate;3-(((dimethylamino)carbonyl)oxy)-n,n,n-trimethyl-benzenaminiumethylsulfat;3-(dimethylcarbamoxy)phenyltrimethylammoniummethylsulfate;ammonium,(m-hydroxyphenyl)trimethyl-,methylsulfate,dimethylcarbamate;Ammonium,[3-(dimethylcarbamoyloxy)phenyl]trimethyl-,methylsulfate
• CAS NO: 51-60-5
• Molecular Formula: CH₃O₄S*C₁₂H₁₉N₂O₂
• Molecular Weight: 334.39
• EINECS: 200-109-5
• Product Categories: Alkaloids;Ammonium Polyhalides, etc. (Quaternary);Quaternary Ammonium Compounds;Intermediates & Fine Chemicals;Pharmaceuticals;Amines;Sulfur & Selenium Compounds
• Mol File: 51-60-5.mol
• Article Data: 4

Chemical Properties

• Melting Point: 175-177 °C(lit.)
• Boiling Point: 457oC
• Appearance: white/powder
• Storage Temp.: −20°C
• Solubility: H2O: 1 g/mL
• Water Solubility: 1g/10mL
• Merck: 14,6464
• CAS DataBase Reference: 3-[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium methyl sulfate(CAS DataBase Reference)
• NIST Chemistry Reference: 3-[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium methyl sulfate(51-60-5)
• EPA Substance Registry System: 3-[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium methyl sulfate(51-60-5)

Safety Data

• Hazard Codes: T+
• Statements: 28-36/37/38-42/43-26/27/28
• Safety Statements: 36-45-36/37/39-28A
• RIDADR: UN 2811 6.1/PG 2
• WGK Germany: 3
• RTECS: CY1225000
• HazardClass: 6.1(a)
• PackingGroup: II
• Hazardous Substances Data: 51-60-5(Hazardous Substances Data)

Usage

Description

3-[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium methyl sulfate, also known as Neostigmine methylsulfate, is a white, crystalline powder with a bitter taste and odorless properties. It is highly soluble in water and soluble in alcohol, making it suitable for use in aqueous solutions. 3-[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium methyl sulfate is hygroscopic, which means it readily absorbs moisture from the environment, and therefore, it is always used in an injectable form. Neostigmine is a reversible inhibitor of acetylcholinesterase (AChE), playing a significant role in various medical applications.

Uses

Used in Pharmaceutical Industry:
Neostigmine methylsulfate is used as a pharmaceutical compound for the treatment of myasthenia gravis and Ogilvie syndrome. It functions by inhibiting the enzyme acetylcholinesterase, which in turn increases the levels of endogenous acetylcholine. This increase in acetylcholine levels helps restore muscle action potentials and improves the symptoms of the mentioned conditions.
Used in Veterinary Medicine:
In a rat model of knee joint inflammation, intrathecal administration of neostigmine (2-30 μg) has been shown to dose-dependently increase the latency of paw withdrawal in response to thermal and mechanical stimuli. This suggests that neostigmine can be used as an analgesic agent in veterinary medicine to manage pain and inflammation in animals.
Used in Research Applications:
Neostigmine methylsulfate is also used in research settings to study the effects of acetylcholinesterase inhibition on various physiological processes. It can be employed in experiments involving neuromuscular junction function, pain perception, and other related areas.
Brand Name:
The brand name for 3-[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium methyl sulfate is Prostigmine (ICN).

Clinical Use

The methylsulfate salt is used postoperatively as a urinarystimulant and in the diagnosis and treatment of myastheniagravis.

Purification Methods

Crystallise the sulfate from EtOH or Me2CO (m 143-144o). Its solubility in H2O is ~10%. [Beilstein 13 III 939.] (It is cholinergic and highly TOXIC.)

InChI:InChI=1/C12H19N2O2.CH4O4S/c1-13(2)12(15)16-11-8-6-7-10(9-11)14(3,4)5;1-5-6(2,3)4/h6-9H,1-5H3;1H3,(H,2,3,4)/q+1;

Synthetic route

norneostigmine (16088-19-0) + dimethyl sulfate (77-78-1) → neostigmine methyl sulfate (51-60-5)

Conditions	Yield
In acetone at 20℃; four neck round bottom flask;	85%
In tetrahydrofuran at 20℃; for 8h;	70%
With acetone
With acetone

Dimethylcarbaminsaeure-3-aminophenylester (19962-04-0) + dimethyl sulfate (77-78-1) → neostigmine methyl sulfate (51-60-5)

Conditions	Yield
With calcium carbonate In acetone at 25 - 30℃; Reagent/catalyst;	84.6%

3-Dimethylaminophenol (99-07-0) → neostigmine methyl sulfate (51-60-5)

Conditions	Yield
Multi-step reaction with 2 steps 2: acetone View Scheme

dimethyl sulfate (77-78-1) + 3-Dimethylaminophenol (99-07-0) + N,N-Dimethylcarbamoyl chloride (79-44-7) → neostigmine methyl sulfate (51-60-5)

Conditions	Yield
Stage #1: 3-Dimethylaminophenol With 18-crown-6 ether; potassium tert-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 40℃; for 0.0583333h; Stage #2: N,N-Dimethylcarbamoyl chloride In tetrahydrofuran; N,N-dimethyl-formamide at 40℃; for 0.00833333h; Stage #3: dimethyl sulfate Further stages;

neostigmine methyl sulfate (51-60-5) + bis(pinacol)diborane (73183-34-3) → (3-((dimethylcarbamoyl)oxy)phenyl)boronic acid

Conditions	Yield
Stage #1: neostigmine methyl sulfate; bis(pinacol)diborane With 10H-phenothiazine; caesium carbonate In acetonitrile for 18h; Irradiation; Sealed tube; Inert atmosphere; Stage #2: With hydrogenchloride; dihydroxy-methyl-borane In acetone Stage #3: With D-Fructose; sodium carbonate In water	74%

Upstream product

• 77-78-1 dimethyl sulfate 
• 99-07-0 3-Dimethylaminophenol 
• 79-44-7 N,N-Dimethylcarbamoyl chloride 
• 19962-04-0 Dimethylcarbaminsaeure-3-aminophenylester 
• 16088-19-0 norneostigmine 

Relevant articles and documents

Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.

PROCESS FOR PREPARATION OF HIGHLY PURE 3-DIMETHYLAMINOPHENYL DIMETHYLCARBAMATE

The invention discloses a novel process for preparation of highly pure 3-dimethylaminophenyl dimethylcarbamate via formation of aryl dimethylcarbamate which can be easily obtained from diaryl carbonate and dimethylamine.