31828-71-4

Basic information

• Product Name: 1-(2,6-Dimethylphenoxy)-2-propanamine
• Synonyms: 1-(2,6-dimethylphenoxy)-2-propanamin;1-methyl-2-(2,6-xylyloxy)-ethylamin;1-Methyl-2-(2,6-xylyloxy)ethylamine;2-Propanamine, 1-(2,6-dimethylphenoxy)-;Ethylamine, 1-methyl-2-(2,6-xylyloxy)-;Mexilitine;1-(2,6-xylyloxy)-2-aminopropane hydrochloride;MEXILETIN
• CAS NO: 31828-71-4
• Molecular Formula: C₁₁H₁₇NO
• Molecular Weight: 179.25878
• EINECS: 250-825-7
• Mol File: 31828-71-4.mol

Chemical Properties

• Melting Point: 203-205 °C
• Boiling Point: 271.5 °C at 760 mmHg
• Flash Point: 112.2 °C
• Appearance: white/powder
• Density: 0.979 g/cm³
• Vapor Pressure: 0.00642mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: ethanol: 50 mg/mL
• PKA: pKa 9.14± 0.01(H2O,t =25±0.2,I=0.01(NaCl))(Approximate)
• CAS DataBase Reference: 1-(2,6-Dimethylphenoxy)-2-propanamine(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(2,6-Dimethylphenoxy)-2-propanamine(31828-71-4)
• EPA Substance Registry System: 1-(2,6-Dimethylphenoxy)-2-propanamine(31828-71-4)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22
• Safety Statements: 36
• RIDADR: 3249
• WGK Germany: 3
• RTECS: KR9300000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 31828-71-4(Hazardous Substances Data)

Usage

Uses

Used in Cardiology:
1-(2,6-Dimethylphenoxy)-2-propanamine is used as an anti-arrhythmic agent for the treatment of ventricular extrasystole, ventricular tachycardia, and ventricular fibrillation, including during the severe period of myocardial infarction. Its cardiac depressant properties help regulate abnormal heart rhythms and maintain a stable heart rate.
Used in Neurology:
1-(2,6-Dimethylphenoxy)-2-propanamine is used as an analgesic agent in the treatment of amyotrophic lateral sclerosis (ALS). It is administered alongside a bile acid and a phenylbutyrate compound, along with an additional therapeutic agent, to alleviate pain and improve the quality of life for ALS patients.
Brand Name:
Mexitil (Boehringer Ingelheim)

Originator

Mexitil,Boehringer Ingelheim,US,1976

Manufacturing Process

The sodium salt of dimethyl phenol was reacted with chloroacetone and this product with hydroxylamine to give the starting material.245 g of this 1-(2',6'-dimethyl-phenoxy)-propanone-(2)-oxime were dissolved in 1,300 cc of methanol, and the solution was hydrogenated at 5 atmospheres gauge and 60°C in the presence of Raney nickel. After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the methanol was distilled out of the filtrate,and the residue, raw 1-(2',6'-dimethylphenoxy)-2-amino-propane, was dissolved in ethanol. The resulting solution was acidified with ethereal hydrochloric acid, the acidic solution was allowed to cool, and the precipitate formed thereby was collected by vacuum filtration. The filter cake was dissolved in ethanol and recystallized therefrom by addition of ether. 140.5 g (51.5% of theory) of a substance having a melting point of 203°C to 205°C were obtained, which was identified to be 1-(2',6'- dimethyl-phenoxy)-2-anino-propane hydrochloride.

Therapeutic Function

Antiarrhythmic

Clinical Use

Mexiletine (Mexitil) is an antiarrhythmic agent with pharmacological and antiarrhythmic properties similar to those of lidocaine and tocainide. Like tocainide,mexiletine is available for oral administration. Mexiletine is useful as an antiarrhythmic agent in the management of patients with either acute or chronic ventricular arrhythmias.While it is not at present an indication for use, there is interest in using mexiletine to treat the congenital long QT syndrome when an abnormality in the SCN5A gene (LQTS 3) has been found.

Side effects

A very narrow therapeutic window limits mexiletine use. The first signs of toxicity manifest as fine tremor of the hands, followed by dizziness and blurred vision. Hypotension, sinus bradycardia, and widening of the QRS complex have been noted as the most common unwanted cardiovascular effects of IV mexiletine. The side effects of oral maintenance therapy include reversible upper gastrointestinal distress, tremor, lightheadedness, and coordination difficulties. These effects generally are not serious and can be reduced by downward dose adjustment or administering the drug with meals. Cardiovascular adverse effects, which are less common, include palpitations, chest pain, and angina or anginalike pain.

Synthesis

Mexiletine is 1-methyl-2-(2,2-dimethylphenoxy)ethylamine (18.1.11). Mexiletine is synthesized by reacting the sodium salt of 2,6-dimethylphenol with chloroacetone, forming 1-(2,6-dimethylphenoxy)-2-propanone (18.1.9). Reacting this with hydroxylamine gives the corresponding oxime (18.1.10). Reduction of the oximine group using hydrogen over Raney nickel gives mexiletine (18.1.11).

Drug interactions

An upward adjustment in dose may be required when mexiletine is administered with phenytoin or rifampin, since these drugs stimulate the hepatic metabolism of mexiletine, reducing its plasma concentration.

Precautions

Mexiletine is contraindicated in the presence of cardiogenic shock or preexisting second- or third-degree heart block in the absence of a cardiac pacemaker. Caution must be exercised in administration of the drug to patients with sinus node dysfunction or disturbances of intraventricular conduction.

InChI:InChI:1S/C11H17NO/c1-8-5-4-6-9(2)11(8)13-7-10(3)12/h4-6,10H,7,12H2,1-3H3

Upstream product

• 72806-53-2 1-(2,6-Dimethylphenoxy)-2-azido-propan 
• 576-26-1 2.6-dimethylphenol 
• 75-55-8 2-Methylaziridine 
• 61102-09-8 (RS)-1-(2,6-dimethylphenoxy)propan-2-ol 
• 68164-74-9 1-(2,6-Dimethylphenoxy)-2-methansulfonyloxy-propan 
• 5370-01-4 (rac)-mexiletine hydrochloride 
• 1092493-53-2 tert-butyl (1-(2,6-dimethylphenoxy)propan-2-yl)carbamate 
• 53012-41-2 (2,6-dimethylphenoxy)-2-propanone 
• 21078-03-5 1,3-dimethyl-2-(prop-2-yn-1-yloxy)benzene 
• 252049-71-1 (2R)-N-(1-(2',6'-dimethylphenoxy)-2-propyl)-(R)-mandelamide 
• 1093278-41-1 (R)-2-[(2,6-dimethylphenoxy)methyl]-1-[(R)-1-phenylethyl]aziridine 
• 1100753-75-0 N-octanoylglycine 2,2,2-trifluoroethyl ester 
• 1051392-84-7 (E)-1-(2,6-dimethyl-phenoxy)-propan-2-one O-benzyl oxime 
• 252049-70-0 (2RS)-N-(1-(2',6'-dimethylphenoxy)-2-propyl)-tetrahydropyranyl-(R)-mandelamide 

Downstream Products

• 93968-89-9 2,2,5,5-tetramethyl-N-[1-(2,6-dimethylphenoxy)propan-2-yl]-2,5-dihydro-1H-pyrrole-3-carboxamide 
• 55304-17-1 N-Hydroxy-Mexiletine 
• 94991-72-7 (S)-mexiletine 
• 31828-71-4 (R)-mexiletine 
• 252049-72-2 (2S)-N-(1-(2',6'-dimethylphenoxy)-2-propyl)-(R)-mandelamide 
• 252049-71-1 (2R)-N-(1-(2',6'-dimethylphenoxy)-2-propyl)-(R)-mandelamide 
• 1043455-56-6 C₁₉H₂₉NO₂ 
• 1105713-18-5 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,6-dimethyl-phenoxy)-1-methyl-ethyl]amide 
• 1105713-19-6 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(4-bromo-2,6-dimethyl-phenoxy)-1-methyl-ethyl]amide 
• 53012-41-2 (2,6-dimethylphenoxy)-2-propanone 
• 1100754-10-6 N-(((S)-1-(2,6-dimethylphenoxy)propan-2-ylcarbamoyl)methyl)octanamide 
• 1190867-98-1 C₂₁H₃₄N₂O₃ 
• 1517-69-7 (R)-1-phenylethanol 
• 107832-32-6 (R)-1-phenylethyl propionate 

Relevant articles and documents

Deracemization of mexiletine biocatalyzed by ω-transaminases

(S)- as well as (R)-mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral orally effective antiarrhythmic agent, was prepared by deracemizatlon starting from the commercially available racemic amine using ω-transaminases In up to >99% ee and conver

Human iPSC-derived cardiomyocytes and pyridyl-phenyl mexiletine analogs

In the United States, approximately one million individuals are hospitalized every year for arrhythmias, making arrhythmias one of the top causes of healthcare expenditures. Mexiletine is currently used as an antiarrhythmic drug but has limitations. The purpose of this work was to use normal and Long QT syndrome Type 3 (LQTS3) patient-derived human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to identify an analog of mexiletine with superior drug-like properties. Compared to racemic mexiletine, medicinal chemistry optimization of substituted racemic pyridyl phenyl mexiletine analogs resulted in a more potent sodium channel inhibitor with greater selectivity for the sodium over the potassium channel and for late over peak sodium current.

Enantiodivergent syntheses of (+)- and (?)-1-(2,6-dimethylphenoxy)propan-2-ol: A way to access (+)- and (?)-mexiletine from D-(+)-mannitol

Chiron approach was used to acquire optically pure (R)- and (S)-1-(2,6-dimethylphenoxy)propan-2-ol, immediate precursors of (S)- and (R)-mexiletines, respectively. Two different routes were followed from a D-mannitol-derived optically pure common precursor to get the enantiomeric alcohols separately. Comparison of their specific rotation values with the corresponding literature values as well as exact mirror-image relationship between their CD curves proved their high enantiopurity. These alcohols were then transformed to the corresponding amine-drugs in an efficient one-step process instead of two steps described in the literature.

Preparation of polar group derivative β-cyclodextrin bonded hydride silica chiral stationary phases and their chromatography separation performances

Three novel β-cyclodextrin compounds derived with piperidine which is flexible, L-proline containing a chiral center, ionic liquid with 3,5-diamino-1,2,4-triazole as the cation were designed and synthesized as chiral selectors for enantiomer separation, whose name were (mono-6-deoxy-6-(piperidine)-β-cyclodextrin, mono-6-deoxy-6-(L-proline)-β-cyclodextrin, mono-6-deoxy-6-(3,5-diamino-1,2,4-triazole)-β-cyclodextrin, multi-substituted 3,5-diamino-1,2,4- triazole-(p-toluenesulfonic)-β-cyclodextrin), respectively. In addition, to enhance the polarity of chiral stationary phases, hydrosilylation and silylation reactions were implemented to derive ordinary silica, the common used selector carrier, to hydride silica, whose surface is covered with proton. 31 pyrrolidine compounds and some chiral drugs were tested in both polar organic mobile phase mode and normal mobile phase mode. 6-Deoxy-6-L-proline-β-cyclodextrin-CSP showed satisfactory separations in polar organic mobile phase mode and exihibited a strong separation capability in different pH values; multi-substituted 3,5-diamino-1,2,4-triazole-(p-toluenesulfonic)-β-cyclodextrin-CSP can separate pyrrolidine compounds in both mobile phase modes with high resolutions and separation efficiency compared to commercially available CSPs, making it to be the most valuable object to study. The composition of mobile phase, type of stationary phase as well as the peak problem of chromatograms was discussed deeply.

Method for synthesizing mexiletine chloride

The invention discloses a method for synthesizing mexiletine chloride, wherein a reaction system takes 2,6-xylenol as a starting material to synthesize a corresponding target product. In the reaction,a transition metal gold complex and a ruthenium complex are used for catalysis, compared with the previous method for synthesizing mexiletine chloride, no alkali is added during a reaction process, no by-products are produced, the reaction atom economy is high, and the reaction conditions are mild. Therefore, the method has broad development prospects.

Production method of mexiletine hydrochloride

The invention provides a production method of mexiletine hydrochloride. The method comprises: a etherification step, namely dissolving 2,6-dimethylphenol in a solid-liquid heterogeneous reaction system to obtain a mixed solution, mixing chloroacetone with the mixed solution, and performing reflux reaction to obtain ether ketone, wherein the solid-liquid heterogeneous reaction system comprises a solvent, a solid-liquid phase transfer promoter, inorganic base and an alkali metal halide; an amination reduction step, namely under suitable reaction conditions, contacting the ether ketone with ammonia methanol to carry out amination reduction reaction to obtain ether amine; and a salting step, namely reacting the ether amine with hydrogen chloride in the solvent to obtain the mexiletine hydrochloride. The method disclosed by the invention improves the reaction efficiency and the production efficiency, and has the advantages of low production cost, small resource consumption and high production efficiency.

Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated Guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

Chiral aziridine ring opening: facile synthesis of (R)-mexiletine and (R)-phenoxybenzamine hydrochloride

Abstract A simple and efficient synthesis of chiral drugs (R)-mexiletine 1, an anti-arrhythmic drug and (R)-phenoxybenzamine hydrochloride 2, an anti-hypertensive drug has been described via controlled reductive ring opening of chiral aziridine as a key step. The target compounds 1 and 2 were obtained in overall yields of 34% and 10.5%, respectively.

CATALYST COMPOUNDS

The present invention relates to an iridium-based catalyst compound for hydrogenating reducible moieties, especially imines and iminiums, the catalyst compounds being defined by the formulas: where ring B is either itself polycyclic, or ring B together with R is polycyclic. The catalysts of the invention are particularly effective in reductive amination procedures 10 which involve the in situ generation of the imine or iminium under reductive hydrogenative conditions.

Continuous flow synthesis of chiral amines in organic solvents: Immobilization of E. coli cells containing both ω-transaminase and PLP

E. coli cells containing overexpressed (R)-selective ω-transaminase and the cofactor PLP were immobilized on methacrylate beads suitable for continuous flow applications. The use of an organic solvent suppresses leaching of PLP from the cells; no addition