137-58-6

Basic information

• Product Name: Lidocaine
• Synonyms: 2-(Diethylamino)-2',6'-acetoxylidide;2-(diethylamino)-2’,6’-acetoxylidide;2-(diethylamino)-n-(2,6-dimethylphenyl)-acetamid;2',6'-Acetoxylidide, 2-(diethylamino)-;6’-acetoxylidide,2-(diethylamino)-2;Acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-;Acetamide,2-(diethylamino)-N-(2,6-dimethylphenyl)-;a-Diethylamino-2,6-acetoxylidide
• CAS NO: 137-58-6
• Molecular Formula: C₁₄H₂₂N₂O
• Molecular Weight: 234.34
• EINECS: 205-302-8
• Product Categories: Research Chemical;Alphacaine, Xylocaine, lignocaine;REGITINE;Other APIs;Pharma materials;API;Halogenated Heterocycles
• Mol File: 137-58-6.mol
• Article Data: 24

Chemical Properties

• Melting Point: 66-69°C
• Boiling Point: bp4 180-182°; bp2 159-160°
• Flash Point: 9℃
• Appearance: White to slightly yellow/powder
• Density: 0.9944 (rough estimate)
• Vapor Pressure: 4.28E-05mmHg at 25°C
• Refractive Index: 1.5110 (estimate)
• Storage Temp.: Store at RT
• Solubility: ethanol: 4 mg/mL
• PKA: pKa 7.88(H2O)(Approximate)
• Water Solubility: practically insoluble
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,5482
• CAS DataBase Reference: Lidocaine(CAS DataBase Reference)
• NIST Chemistry Reference: Lidocaine(137-58-6)
• EPA Substance Registry System: Lidocaine(137-58-6)

Safety Data

• Hazard Codes: Xn,T,F
• Statements: 22-39/23/24/25-23/24/25-11
• Safety Statements: 22-26-36-45-36/37-16-7
• RIDADR: 3249
• WGK Germany: 3
• RTECS: AN7525000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 137-58-6(Hazardous Substances Data)

Usage

description

Lidocaine is a local anesthetic, also known as Xylocaine, in recent years it has been replaced procaine, widely used in local infiltration anesthesia in cosmetic plastic surgery, it can block the nerve excitability and conduction by inhibiting the sodium channels of nerve cell membrane. The fat soluble and protein binding rate of lidocaine is higher than procaine, its cell penetrating ability is strong, fast onset, long duration of action, the interaction strength is 4 times of procaine. Lidocaine is used in infiltration anesthesia, epidural anesthesia, topical anesthesia (including thoracoscopy or abdominal surgery for mucosal anesthesia) and nerve block. In order to extend the time of anesthesia, reduce the poisoning of lidocaine and other side effects, can be added in the anesthetic epinephrine. Lidocaine can also be used for the treatment of ventricular premature beat after acute myocardial infarction, ventricular tachycardia, digitalis poisoning, cardiac surgery and cardiac catheterization-induced ventricular arrhythmias, including ventricular premature beats, ventricular tachycardia and ventricular fibrillation. Lidocaine is also used for duration status of epilepsy which other anti-seizure drugs are not effective, as well as local or spinal anesthesia. But it is usually ineffective for supraventricular arrhythmias.

Chemical property

Lidocaine is white needle like crystals, and its melting point is 68-69℃; boiling point is 180-182℃ (0.53kPa), soluble in ethanol in 159-160℃ (0.267kPa), ether, benzene, chloroform and oil, do not dissolve in water. In common use radical hydrochloride, lidocaine hydrochloride (C14H22N2O ? HCL, [73-78-9]) is a white crystalline powder. Melting point 127-129℃, and the monohydrate melting point is 77-78℃. Easily soluble in water, 0.5% aqueous solution pHO 4.0-5.5. Odorless, bitter taste.

Uses

Different sources of media describe the Uses of 137-58-6 differently. You can refer to the following data:
1. Lidocaine is an Anesthetic (local); antiarrhythmic (class IB). Long-acting, membrane stabilizing agent against ventricular arrhythmia. Originally developed as a local anesthetic. Neuroprotective & Neuroresearch Products. Lidocaine is widely used in surface anesthesia, anesthesia, conduction anesthesia and epidural anesthesia. The LD50 of oral lidocaine hydrochloride to mice was 290 mg/kg.
2. Lidocaine is used in creams and lotions to soothe areas of inflamed skin or for example in hemorrhoid preparations to reduce discomfort; used by doctors to anesthetise areas prior to surgery, often avoiding the need for a general anesthetie; used by injection after a heart attack to treat some rhythm disturbances.
3. Lidocaine (Alphacaine)is a selective inverse peripheral histamine H1-receptor agonist with an IC50 of >32 μM. [1] Histamine is responsible for many features of allergic reactions. Lidocaine (Alphacaine)is a second-generation antihistamine agent closely st
4. Antiarrhythmic Agents, Anesthetics；Anticonvulsant；antihypertensive

Description

Lidocaine [2-(diethylamino)-N-(2, 6-dimethylphenyl) acetamide monohydrochloride] is the most commonly used amino amide-type local anesthetic. Lidocaine is very lipid soluble and, thus, has a more rapid onset and a longer duration of action than most amino ester-type local anesthetics, such as procaine and tetracaine. It can be administered parenterally (with or without epinephrine) or topically either by itself or in combination with prilocaine or etidocaine as a eutectic mixture that is very popular with pediatric patients. The use of lidocaine–epinephrine mixtures should be avoided, however, in areas with limited vascular supply to prevent tissue necrosis. Lidocaine also frequently is used as a class IB antiarrhythmic agent for the treatment of ventricular arrhythmias, both because it binds and inhibits sodium channels in the cardiac muscle and because of its longer duration of action than amino ester-type local anesthetics. Central nervous system changes are the most frequently observed systemic toxicities of lidocaine. The initial manifestations are restlessness, vertigo, tinnitus, slurred speech, and eventually, seizures. Subsequent manifestations include CNS depression with a cessation of convulsions and the onset of unconsciousness and respiratory depression or cardiac arrest. This biphasic effect occurs because local anesthetics initially block the inhibitory GABAergic pathways, resulting in stimulation, and eventually block both inhibitory and excitatory pathways (i.e., block the sodium channels associated with the NMDA receptors, resulting in overall CNS inhibition).

Chemical Properties

solid

Originator

Xylocaine,Astra,US,1949

Definition

ChEBI: Lidocaine is the monocarboxylic acid amide resulting from the formal condensation of N,N-diethylglycine with 2,6-dimethylaniline. It has a role as a local anaesthetic, an anti-arrhythmia drug, an environmental contaminant, a xenobiotic and a drug allergen. It is a monocarboxylic acid amide, a tertiary amino compound and a member of benzenes. It derives from a glycinamide.

Indications

Experimentally, lidocaine has been found to prevent VF arising during myocardial ischemia or infarction by preventing the fragmentation of organized largewavefronts into heterogeneous wavelets. Although lidocaine is of proven benefit in preventing VF early after clinical myocardial infarction, there is no evidence that it reduces mortality. To the contrary, lidocaine may increase mortality after myocardial infarction by approximately 40% to 60%.There are no controlled studies of lidocaine in secondary prevention of recurrence of VT or VF. Lidocaine terminates organized monomorphic spontaneous VT or induced sustained VT in only approximately 20% of cases and is less effective than many other antiarrhythmic drugs. In a blinded, randomized study of intravenous lidocaine versus intravenous amiodarone in out-of-hospital VF resistant to defibrillation, lidocaine was associated with half the likelihood of survival to hospital admission compared with amiodarone.

Manufacturing Process

One mol of 2,6-xylidine is dissolved in 800 ml glacial acetic acid. The mixture is cooled to 10°C, after which 1.1 mol chloracetyl chloride is added at one time. The mixture is stirred vigorously during a few moments after which 1,000 ml half-saturated sodium acetate solution, or other buffering or alkalizing substance, is added at one time. The reaction mixture is shaken during half an hour. The precipitate formed which consists of ω-chloro-2,6- dimethyl-acetanilide is filtered off, washed with water and dried. The product is sufficiently pure for further treatment. The yield amounts to 70 to 80% of the theoretical amount.One mole of the chloracetyl xylidide thus prepared and 2.5 to 3 mols diethyl amine are dissolved in 1,000 ml dry benzene. The mixture is refluxed for 4 to 5 hours. The separated diethyl amine hydrochloride is filtered off. The benzene solution is shaken out two times with 3N hydrochloric acid, the first time with 800 ml and the second time with 400 ml acid. To the combined acid extracts is added an approximately 30% solution of sodium hydroxide until the precipitate does not increase.The precipitate, which sometimes is an oil, is taken up in ether. The ether solution is dried with anhydrous potassium carbonate after which the ether is driven off. The remaining crude substance is purified by vacuum distillation. During the distillation practically the entire quantity of the substance is carried over within a temperature interval of 1° to 2°C. The yield approaches the theoretical amount. MP 68° to 69°C. BP 180° to 182°C at 4 mm Hg; 159° to 160°C at 2 mm Hg. (Procedure is from US Patent 2,441,498.)

Brand name

Alphacaine (Carlisle); Lidoderm (Teikoku); Xylocaine (AstraZeneca）.

Therapeutic Function

Local anesthetic, Antiarrhythmic

General Description

Lidocaine was the first amino amide synthesized in 1948and has become the most widely used local anesthetic. Thetertiary amine has a pKa of 7.8 and it is formulated as thehydrochloride salt with a pH between 5.0 and 5.5. When lidocaineis formulated premixed with epinephrine the pH ofthe solution is adjusted to between 2.0 and 2.5 to prevent the hydrolysis of the epinephrine. Lidocaine is also availablewith or without preservatives. Some formulations of lidocainecontain a methylparaben preservative that maycause allergic reactions in PABA-sensitive individuals. Thelow pKa and medium water solubility provide intermediateduration of topical anesthesia of mucous membranes.Lidocaine can also be used for infiltration, peripheral nerveand plexus blockade, and epidural anesthesia.

Biological Activity

Anasthetic and class Ib antiarrhythmic agent.? Blocks voltage-gated sodium channels in the inactivated state.

Contact allergens

Lidocaine is an anesthetic of the amide group, like articaine or bupivacaine. Immediate-type IgE-dependent reactions are rare, and delayed-type contact dermatitis is exceptional. Cross-reactivity between the different amide anesthetics is not systematic.

Biochem/physiol Actions

Na+ channel blocker; class IB antiarrhythmic that is rapidly absorbed after parenteral administration.

Pharmacology

Lidocaine is the most widely used local anaesthetic. It has a rapid onset and short duration of action. Lidocaine is rapidly and extensively metabolised in the liver and is safe at recommended doses. Efficacy is enhanced markedly and duration of action prolonged by addition of adrenaline. Lidocaine is less toxic than bupivacaine; a testament to this relative safety is that lidocaine is used intravenously as a class 1b antiarrhythmic and as an i.v. infusion to treat refractory chronic pain. Lidocaine solutions for injection are available in concentrations of 1% and 2%, with or without adrenaline. It is also available as a spray (4% or 10%), cream (2% or 4%), ointment or medicated plaster (both 5%) for topical application.

Pharmacokinetics

Lidocaine is administered intravenously because extensive first-pass transformation by the liver prevents clinically effective plasma concentrations orally. The drug is dealkylated and eliminated almost entirely by the liver; therefore, dosage adjustments are necessary in the presence of hepatic disease or dysfunction. Lidocaine clearance exhibits the time dependency common to high-clearance agents. With a continuous infusion lasting more than 24 hours, there is a decrease in total lidocaine clearance and an increase in elimination half-life compared with a single dose. Lidocaine free plasma levels can vary in certain patients owing to binding with albumin and the acutephase reactant a1-acid glycoprotein. Levels of a1-acid glycoprotein are increased in patients after surgery or acute myocardial infarction, whereas levels of both a1-acid glycoprotein and serum albumin are decreased in chronic hepatic disease or heart failure and in those who are malnourished. This is an essential consideration because it is the unbound fraction that is pharmacologically active.

Clinical Use

The metabolism of lidocaine is typical of the amino amideanesthetics . The liver is responsiblefor most of the metabolism of lidocaine and any decreasein liver function will decrease metabolism. Lidocaineis primarily metabolized by de-ethylation of the tertiary nitrogento form monoethylglycinexylidide (MEGX). At lowlidocaine concentrations, CYP1A2 is the enzyme responsiblefor most MEGX formation. At high lidocaine concentrations,both CYP1A2 and CYP3A4 are responsible for the formationof MEGX.

Side effects

Central nervous system side effects such as drowsiness, slurred speech, paresthesias, agitation, and confusion predominate. These symptoms may progress to convulsions and respiratory arrest with higher plasma concentrations. A rare adverse effect is malignant hyperthermia. Cimetidine significantly reduces the systemic clearance of lidocaine as well as the volume of distribution at steady state and the degree of plasma protein binding. Beta blockers also reduce lidocaine clearance owing to a decrease in hepatic blood flow. For the same reason, clearance is reduced in congestive heart failure or low-output states. Amiodarone may also influence the pharmacokinetics of lidocaine. In patients receiving amiodarone, single doses of intravenous lidocaine do not influence the pharmacokinetics of either agent. When amiodarone treatment is started in patients who are already receiving lidocaine infusion, there is a decrease in lidocaine clearance, which can result in toxic lidocaine levels.

Safety Profile

Poison by ingestion, intravenous, intraperitoneal, and subcutaneous routes. Human systemic effects: blood pressure lowering, changes in heart rate, coma, convulsions, dlstorted perceptions, dyspnea, excitement, hallucinations, muscle contraction or spasticity, pulse rate, respiratory depression, toxic psychosis. An experimental teratogen. Other experimental reproductive effects. A local anesthetic. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Lidocaine, 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (2.2.2), is synthesized from 2,6-dimethylaniline upon reaction with chloroacetic acid chloride, which gives α-chloro-2,6-dimethylacetanilide (2.1.1), and its subsequent reaction with diethylamine [11].

Veterinary Drugs and Treatments

Besides its use as a local and topical anesthetic agent, lidocaine is used to treat ventricular arrhythmias, principally ventricular tachycardia and ventricular premature complexes in all species. Cats may be more sensitive to the drug and some clinicians feel that it should not be used in this species as an antiarrhythmic, but this remains controversial. In horses, lidocaine may be useful to prevent postoperative ileus and reperfusion injury.

Electrophysiologic Effects

Experimentally, lidocaine has been found to prevent VF arising during myocardial ischemia or infarction by preventing the fragmentation of organized largewavefronts into heterogeneous wavelets. Although lidocaine is of proven benefit in preventing VF early after clinical myocardial infarction, there is no evidence that it reduces mortality. To the contrary, lidocaine may increase mortality after myocardial infarction by approximately 40% to 60%.There are no controlled studies of lidocaine in secondary prevention of recurrence of VT or VF. Lidocaine terminates organized monomorphic spontaneous VT or induced sustained VT in only approximately 20% of cases and is less effective than many other antiarrhythmic drugs. In a blinded, randomized study of intravenous lidocaine versus intravenous amiodarone in out-of-hospital VF resistant to defibrillation, lidocaine was associated with half the likelihood of survival to hospital admission compared with amiodarone.

Drug interactions

The concurrent administration of lidocaine with cimetidine but not ranitidine may cause an increase (15%) in the plasma concentration of lidocaine. This effect is a manifestation of cimetidine reducing the clearance and volume of distribution of lidocaine. The myocardial depressant effect of lidocaine is enhanced by phenytoin administration.

Metabolism

Lidocaine is extensively metabolized in the liver by N-dealkylation and aromatic hydroxylations catalyzed by CYP1A2 isozymes. Lidocaine also possesses a weak inhibitory activity toward the CYP1A2 isozymes and, therefore, may interfere with metabolism of other medications.

Toxicity evaluation

The potency of lidocaine depends on various factors including age of the subject, weight, physique including obesity, vascularity of the site, and indication for use, as this would determine the absorption and excretion rate. Physiologically, lidocaine blocks neuronal transmission by interfering with the flow of sodium across excitable membranes. A single lidocaine molecule binds to a single voltage-gated sodium channel impeding the movement of sodium ions across neuronal membranes. Consequently repolarization is prevented and further depolarization is not possible. Toxicity is dose related and results from excessive quantities of lidocaine.

Precautions

Contraindications include hypersensitivity to local anesthetics of the amide type (a very rare occurrence), severe hepatic dysfunction, a history of grand mal seizures due to lidocaine, and age 70 or older. Lidocaine is contraindicated in the presence of second- or thirddegree heart block, since it may increase the degree of block and can abolish the idioventricular pacemaker responsible for maintaining the cardiac rhythm.

InChI:InChI=1/C14H22N2O/c1-5-16(6-2)10-13(17)15-14-11(3)8-7-9-12(14)4/h7-9H,5-6,10H2,1-4H3,(H,15,17)/p+1

Synthetic route

diethylamine (109-89-7) + 2-chloro-N-(2,6-dimethylphenyl)acetamide (1131-01-7) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 99℃; under 5171.62 Torr; Temperature; Flow reactor;	98%
at 40℃; for 6h; Temperature;	97%
In hexane at 60℃; Temperature; Reflux;	91.1%

diethylamine (109-89-7) + chloroacetyl chloride (79-04-9) + 2,6-dimethylaniline (87-62-7) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
Stage #1: chloroacetyl chloride; 2,6-dimethylaniline In toluene at 80 - 90℃; for 3h; Large scale; Stage #2: With sodium carbonate; potassium iodide In water; toluene for 0.5h; Large scale; Stage #3: diethylamine In water; toluene Solvent; Temperature; Reagent/catalyst; Large scale;	95.2%
With potassium hydroxide In 1-methyl-pyrrolidin-2-one at 120 - 130℃; under 12929 Torr;

(2-diethylaminoethyl)amide (7409-48-5) + 2,6-dimethylaniline (87-62-7) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
With dipotassium peroxodisulfate In water at 100℃; for 0.166667h; Microwave irradiation; Green chemistry;	95%

denatonium benzoate (3734-33-6) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 2-diethylamino-N-(2,6-dimethyl-phenyl)-3-phenyl-propionamide

Conditions	Yield
at 250℃;

2,6-dimethylaniline (87-62-7) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; sodium acetate 2: benzene View Scheme
Multi-step reaction with 2 steps 1: triethylamine / chloroform / 0.02 h / Flow reactor 2: triethylamine / N,N-dimethyl-formamide / 0.19 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1: acetic acid; sodium acetate / water / 24 h / Reflux 2: triethylamine / 1,4-dioxane / 120 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: dichloromethane / 105 °C / 12929 Torr / Flow reactor 2: triethylamine / N,N-dimethyl-formamide / 99 °C / 5171.62 Torr / Flow reactor View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 3 h / 20 °C 2: acetone / 8 h / Reflux View Scheme

[(2,6-dimethylphenylcarbamoyl)methyl]diethyl-(2-phosphonooxybenzyl)ammonium trifluoroacetate disodium salt → salicylic alcohol (90-01-7) + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
With alkaline phosphatase In water at 37℃; for 6h; pH=7.4; Enzyme kinetics; Enzymatic reaction;

[(2,6-dimethylphenylcarbamoyl)methyl]diethyl-(2-phosphonooxybenzyl)ammonium trifluoroacetate disodium salt → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
With rat lung homogenate at 37℃; for 3h; Enzyme kinetics;

[(2,6-dimethylphenylcarbamoyl)methyl]diethyl-(4-phosphonooxybenzyl)ammonium trifluoroacetate disodium salt → (4-hydroxyphenyl)methanol (623-05-2) + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
With alkaline phosphatase In water at 37℃; for 6h; pH=7.4; Enzyme kinetics; Enzymatic reaction;

C14H22N2O*C56H98O35 (178421-96-0) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + heptakis(2,6-di-O-methyl)cyclomaltoheptaose (51166-71-3)

Conditions	Yield
With pluronic copolymer F290 In water at 25℃; Equilibrium constant; Reagent/catalyst;

N,N-diethylglycine methyl ester (30280-35-4) + 2,6-dimethylaniline (87-62-7) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
With sodium methylate at 95℃; for 0.5h; Concentration; Temperature;

2.6-dimethylphenol (576-26-1) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium hydroxide; 2,6-dimethylcyclohexanone; 5%-palladium/activated carbon / 5 h / 180 °C 2: sodium methylate / 0.5 h / 95 °C View Scheme

2,6-dimethylnitrobenzene (81-20-9) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 5%-palladium/activated carbon; hydrogen / methanol / 20 - 25 °C 2.1: potassium carbonate / dichloromethane 2.2: 1 h / 20 °C 3.1: hexane / 60 °C / Reflux View Scheme

2-(N-ethylacetamido)2',6'-dimethylacetanilide → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
With borane-THF In tetrahydrofuran at 20℃;	176 mg

2,6-dimethylphenyl isonitrile (119072-54-7, 2769-71-3) → 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,2-dichloro-ethane / 45 °C 2: borane-THF / tetrahydrofuran / 20 °C View Scheme

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + stearic acid (57-11-4) → C14H22N2O*C18H36O2 (1001438-56-7)

Conditions	Yield
for 0.0833333h; Inert atmosphere; Heating;	100%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → lidocaine hydrochloride (73-78-9)

Conditions	Yield
With hydrogenchloride In diethyl ether	100%
With hydrogenchloride; pyrographite In water; 1,2-dichloro-ethane for 0.333333h; pH=3.5; pH-value;	88.72%
With hydrogenchloride In water; acetone at 20℃; pH=<= 4;	80.6%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (150994-82-4) → 2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoate

Conditions	Yield
In acetonitrile at 50℃; for 6h;	100%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → C14H17(2)H5N2O

Conditions	Yield
With [(2)H6]acetone; tris(pentafluorophenyl)borate In toluene at 150℃; for 3h; Inert atmosphere;	99%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + bromoacetic acid methyl ester (96-32-2) → 2-((2,6-dimethylphenyl)amino)-N,N-diethyl-N-(2-methoxy-2-oxoethyl)-2-oxoethan-1-aminium bromide

Conditions	Yield
In acetonitrile at 80℃; for 1h; Inert atmosphere;	97%
In acetonitrile at 60℃;

gluconic acid (526-95-4) + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → 2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoate

Conditions	Yield
In ethanol for 5h; pH=2 - 7;	95%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → N-(4-chloro-2,6-dimethylphenyl)-2-(diethylamino)-acetamide

Conditions	Yield
With trichloroisocyanuric acid; brilliant green carbocation In acetonitrile at 20℃; for 0.166667h; Irradiation; regioselective reaction;	94%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → lidocaine N-oxide (2903-45-9)

Conditions	Yield
With perfluoro-cis-2-n-butyl-3-n-propyloxaziridine; HCFC-225ca,cb In dichloromethane at -60℃; for 0.333333h;	93%
With dihydrogen peroxide In methanol at 20℃; for 42h;	71%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane
With rat liver microsomes; NADPH In water Product distribution;

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + (4-bromomethylbenzyl)carbamic acid tert-butyl ester (187283-17-6) → C27H40N3O3(1+)*Br(1-)

Conditions	Yield
at 80℃; for 0.166667h;	91%
at 80℃; for 0.166667h;	91%

acetoxymethyl bromide (590-97-6) + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → N-(acetoxymethyl)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium bromide

Conditions	Yield
In acetonitrile at 80℃; for 1h; Inert atmosphere;	90%
In 1,2-dichloro-ethane at 100℃; for 6h; Sealed tube;	40%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 4-tetradecylbenzenesulfonic acid (47377-16-2) → lidocaine 4-tetradecylbenzenesulfonate

Conditions	Yield
In isopropyl alcohol Heating;	90%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + tetramethylammonium fluoride (373-68-2) → 2-(diethylamino)-N-(2,6-dimethylphenyl)-N-methylacetamide (31058-85-2)

Conditions	Yield
In toluene at 100℃; for 12h;	88%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 4-octadecylbenzenesulfonic acid (79840-57-6) → lidocaine 4-octadecylbenzenesulfonate

Conditions	Yield
In ethanol; water Heating;	87%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → 2-diethylamino-N-(2,6-dimethyl-3-nitro-phenyl)-acetamide (39942-49-9)

Conditions	Yield
With sulfuric acid; nitric acid In water at 0 - 25℃; for 0.75h;	86%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + C31H60O8S*C5H5N → C31H60O8S*C14H22N2O

Conditions	Yield
In methanol at 20℃; for 0.5h;	85%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → C14H15(2)H7N2O

Conditions	Yield
With d8-isopropanol; 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II) In toluene at 170℃; for 2h; Inert atmosphere; Microwave irradiation; Sealed tube;	84%
With 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II); d8-isopropanol In toluene at 170℃; under 12751.3 Torr; for 2h; Microwave irradiation; Inert atmosphere; Sealed tube;	84%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → C14H20(2)H2N2O

Conditions	Yield
With tetrakis(tetrabutylammonium)decatungstate(VI); 2,4,6-Triisopropylthiophenol; water-d2; trifluoroacetic acid In acetonitrile Irradiation;	84%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + (2,6-dichlorophenyl)cyanamide (21714-23-8) + palladium diacetate (3375-31-3) → K[Pd(2,6-Cl2pcyd)2(LC)]

Conditions	Yield
Stage #1: (2,6-dichlorophenyl)cyanamide With potassium hydroxide In ethanol Reflux; Stage #2: 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide; palladium diacetate With triethylamine In ethanol at 20℃; for 48h; pH=7;	83.33%

ammonium hexafluorophosphate + [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 (52462-29-0) + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → C24H36ClN2ORu(1+)*F6P(1-)

Conditions	Yield
Stage #1: [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide In acetone at 20℃; for 5h; Inert atmosphere; Schlenk technique; Stage #2: ammonium hexafluorophosphate Inert atmosphere; Schlenk technique;	81.2%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 2-bromoethanol (540-51-2) → 2-(2,6-dimethylphenylamino)-N,N-diethyl-N-(2-hydroxyethyl)-2-oxoethanaminium bromide

Conditions	Yield
at 100℃; for 8h;	81.2%
at 90℃; for 24h; Temperature; Sealed tube;	31%
at 90℃; for 24h;	27.6%
at 80℃;

2,6-dimethylphenylcyanamide (20922-60-5) + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + palladium diacetate (3375-31-3) → K[Pd(2,6-Me2pcyd)2(LC)]

Conditions	Yield
Stage #1: 2,6-dimethylphenylcyanamide With potassium hydroxide In ethanol Reflux; Stage #2: 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide; palladium diacetate With triethylamine In ethanol at 20℃; for 48h; pH=7;	81.14%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 1-bromo-3-propanol (627-18-9) → N-(2-(2,6-dimethylphenylamino)-2-oxoethyl)-N,N-diethyl-3-hydroxypropan-1-aminium bromide

Conditions	Yield
at 110℃; for 8h;	80.3%
at 80℃;

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 2,6-diethylphenylcyanamide + palladium diacetate (3375-31-3) → K[Pd(2,6-Et2pcyd)2(LC)]

Conditions	Yield
Stage #1: 2,6-diethylphenylcyanamide With potassium hydroxide In ethanol Reflux; Stage #2: 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide; palladium diacetate With triethylamine In ethanol at 20℃; for 48h; pH=7;	79.25%

potassium cyanide + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → 2-((1-cyanoethyl)(ethyl)amino)-N-(2,6-dimethyl-phenyl)acetamide

Conditions	Yield
With 2-Picolinic acid; iron(III) chloride; tert-Butyl peroxybenzoate; 18-crown-6 ether In acetonitrile at 50℃; for 48h;	77%

dichlorobis(dimethyl sulfoxide)platinum(II) + 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + 3,5-dichlorophenylcyanamide + potassium hydroxide → K[Pt(3,5-(Cl2)2pcyd)2(LC)]

Conditions	Yield
Stage #1: 3,5-dichlorophenylcyanamide; potassium hydroxide In ethanol Reflux; Stage #2: dichlorobis(dimethyl sulfoxide)platinum(II); 2-diethylamino-N-(2,6-dimethylphenyl)-acetamide With triethylamine In ethanol at 20℃; pH=Ca. 7;	76.55%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) → N-(3-chloro-2,6-dimethylphenyl)-2-(diethylamino)acetamide

Conditions	Yield
With hydrogen fluoride; antimony pentafluoride; sodium chloride at -20℃;	75%
With hydrogenchloride; [bis(acetoxy)iodo]benzene In water; 1,2-dichloro-ethane at 50℃; for 2h; Reagent/catalyst; regioselective reaction;	60%

2-diethylamino-N-(2,6-dimethylphenyl)-acetamide (137-58-6) + acetic anhydride (108-24-7) → 2-(N-ethylacetamido)2',6'-dimethylacetanilide

Conditions	Yield
With 1H-imidazole; iodosylbenzene; chloro(meso-tetrakis(2,6-dichlorophenyl)porphyrinato)manganese(III) In dichloromethane; acetonitrile at 20℃; for 3h;	74%

Upstream product

• 3734-33-6 denatonium benzoate 
• 30280-35-4 N,N-diethylglycine methyl ester 
• 87-62-7 2,6-dimethylaniline 
• 576-26-1 2.6-dimethylphenol 
• 2644-21-5 ethyl N,N-diethylglycinate 
• 81-20-9 2,6-dimethylnitrobenzene 
• 178421-96-0 C₁₄H₂₂N₂O*C₅₆H₉₈O₃₅ 
• 109-89-7 diethylamine 
• 1131-01-7 2-chloro-N-(2,6-dimethylphenyl)acetamide 
• 79-04-9 chloroacetyl chloride 
• 7409-48-5 (2-diethylaminoethyl)amide 
• 119072-54-7 2,6-dimethylphenyl isonitrile 

Downstream Products

• 24003-58-5 Lidocaine N-ethyl bromide 
• 5369-03-9 QX-314 
• 75889-35-9 2-Diethylamino-N-(2,6-dimethyl-phenyl)-N-(2-ethoxy-ethyl)-acetamide 
• 75889-33-7 2-Diethylamino-N-(2,6-dimethyl-phenyl)-N-(2-hydroxy-ethyl)-acetamide 
• 1674-99-3 denatonium chloride 
• 39942-49-9 2-diethylamino-N-(2,6-dimethyl-3-nitro-phenyl)-acetamide 
• 1044658-01-6 N-(3-bromo-2,6-dimethyl-phenyl)-2-diethylamine-acetamide 
• 178421-96-0 C₁₄H₂₂N₂O*C₅₆H₉₈O₃₅ 
• 145089-38-9 lidocaine monodecanoic acid salt 
• 1001438-56-7 C₁₄H₂₂N₂O*C₁₈H₃₆O₂ 
• 1206879-80-2 lidocaine monohexanoic acid salt 
• 178421-95-9 C₁₄H₂₂N₂O*C₄₂H₇₀O₃₅ 
• 73-78-9 lidocaine hydrochloride 

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Relevant articles and documents

1,3,5-Triazinanes as Formaldimine Surrogates in the Ugi Reaction

In the present study, a new synthetic strategy towards N-acylated glycinamides was developed by the use of 1,3,5-triazinanes as formaldimine surrogates in the Ugi reaction. The targeted products were obtained in a combinatorial, diversity-oriented fashion in good yields. Further modifications allowed us to adapt this procedure for the one-pot two-step syntheses of a local anesthetic druglidocaine and several unsymmetrically substituted diketopiperazines.

Direct injection gas chromatographic/mass spectrometric analysis for denatonium benzoate in specific denatured alcohol formulations

Direct injection GC/MS was investigated for the analysis of benzyldiethyl(2,6-xylylcarbamoylmethyl)ammonium benzoate (Bitrex), a quaternary ammonium salt, in various Canadian denatured alcohol formulations. Bitrex yielded predominantly a peak due to the neutral diethylamine derivative (I). The structure of I, elucidated by MS and NMR, is strongly related to that of the cation of Bitrex. Compound I was formed from Bitrex in the heated injector port of the GC via a decomposition reaction similar to Stevens rearrangement. The response of I was found to be dependent on the injector port temperature, and the optimal temperature was determined to be in the range 250-350°C. The GC/MS response of I in SIM mode was used to quantify Bitrex. The effects of the codenaturants sucrose octaacetate (SOA), diethyl phthalate (DEP), and camphor, which are present at much higher concentration than Bitrex in several formulations, were also investigated. The presence of SOA enhanced the response of the analyte considerably, while DEP and camphor had no significant effect. All standard curves of Bitrex (1-16 ppm) in different alcohol matrixes were fitted by second-order polynomial functions, with coefficients of determination (R2) routinely in the range 0.998-0.999. The analysis time was 18 min, and the within-run precision was 4%. The results of this study point to the potential of the GC/MS technique as a quantitative tool for Bitrex in various alcohol formulations.

Carboxyesterase polypeptides for amide coupling

The present invention provides engineered carboxyesterase enzymes having improved properties as compared to a naturally occurring wild-type carboxyesterase enzymes, as well as polynucleotides encoding the engineered carboxyesterase enzymes, host cells capable of expressing the engineered carboxyesterase enzymes, and methods of using the engineered carboxyesterase enzymes in amidation reactions.

Method for preparing lidocaine

The invention discloses a method for preparing lidocaine. The method comprises the following steps of: (1) by using 2, 6-dimethylnitrobenzene as a raw material, Pd/C as a catalyst and methanol as a solvent, carrying out reduction reaction with hydrogen at normal temperature and normal pressure to obtain an intermediate 2, 6-dimethylaniline; (2) reacting the obtained intermediate 2, 6-dimethylaniline with chloroacetyl chloride in the presence of potassium carbonate, and taking dichloromethane as a solvent to prepare an intermediate chloroacetyl-2, 6-dimethylaniline; and (3) reacting the obtained intermediate chloroacetyl-2, 6-dimethylaniline with diethylamine, taking normal hexane as a solvent, performing refluxing until the reaction is complete, performing washing with water and cooling toobtain lidocaine. The method disclosed by the invention is simple and convenient in technological process, few in operation links and relatively high in lidocaine yield, and the prepared lidocaine isgood in purity which reaches 99.5% or above, so that the method has a good industrial application prospect.