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Etomidate structure
Etomidate structure

Etomidate

Iupac Name:ethyl 3-(1-phenylethyl)imidazole-4-carboxylate
CAS No.: 33125-97-2
Molecular Weight:244.294
Modify Date.: 2022-03-11 16:07
Introduction: Etomidate is a carboxylated imidazole intended for the inductionof general anesthesia. It is marketed as the morepotent R (+) isomer. It is believed to exert its anestheticeffect via positive modulation of the GABAA receptor. Itis not water soluble and is available in the United States as a2-mg/mL solution containing 35% v/v propylene glycol andin Europe as a soybean oil and medium-chain triglyceridesformulation. The propylene glycol has been associatedwith moderate-to-severe pain on injection and irritation ofthe vascular tissue. A high incidence of skeletal musclemovements were noted in about 32% of patients followingetomidate injection. Case reports of seizures are also foundin the literature. View more+
1. Names and Identifiers
1.1 Name
Etomidate
1.2 Synonyms

(+)-Ethyl 1-(α-methylbenzyl)imidazole-5-carboxylate (R)-(+)-1-(1-Phenylethyl)-1H-imidazole-5-carboxylic Acid Ethyl Ester (r)-(+)-1-(alpha-methylbenzyl)imidazole-5-carboxylicacidethylester (R)-(+)-1-(α-Methylbenzyl)imidazole-5-carboxylic acid ethyl ester (R)-1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid ethyl ester (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate 1-(1-phenylethyl)-,ethylester,(r)-1h-imidazole-5-carboxylicaci 1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid ethyl ester 1-(1-phenylethyl)-1h-imidazole-5-carboxylicacidethylester 1-[(R)-α-Methylbenzyl]-1H-imidazole-5-carboxylic acid ethyl ester 1H-Imidazole-5-carboxylic acid, 1-((1R)-1-phenylethyl)-, ethyl ester 1H-Imidazole-5-carboxylic acid, 1-(1-phenylethyl)-, ethyl ester, (R)- 1H-Imidazole-5-carboxylic acid, 1-[(1R)-1-phenylethyl]-, ethyl ester AMIDATE Amidate R16659 Amidate, R16659 Amidate,R16659 D-ETOMIDATE EINECS 251-385-9 Ethyl (R)-(+)-1-(1-Phenylethyl)-1H-imidazole-5-carboxylate Ethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate ethyl 3-[(1R)-1-phenylethyl]imidazole-4-carboxylate Etomidate (200 mg) HYPNOMIDATE Imidazole-5-carboxylic acid, 1-(alpha-methylbenzyl)-, ethyl ester, (R)-(+) Imidazole-5-carboxylic acid, 1-(α-methylbenzyl)-, ethyl ester, (R)-(+)- MFCD00869295 PROPISCIN R-(+)-Ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate R-1665 RADENARCON

1.3 CAS No.
33125-97-2
1.4 CID
667484
1.5 EINECS(EC#)
251-385-9
1.6 Molecular Formula
C14H16N2O2 (isomer)
1.7 Inchi
InChI=1S/C14H16N2O2/c1-3-18-14(17)13-9-15-10-16(13)11(2)12-7-5-4-6-8-12/h4-11H,3H2,1-2H3/t11-/m1/s1
1.8 InChkey
NPUKDXXFDDZOKR-LLVKDONJSA-N
1.9 Canonical Smiles
CCOC(=O)C1=CN=CN1C(C)C2=CC=CC=C2
1.10 Isomers Smiles
CCOC(=O)C1=CN=CN1[C@H](C)C2=CC=CC=C2
2. Properties
3.1 Density
1.11
3.1 Melting point
72-74°C
3.1 Boiling point
391.5°Cat760mmHg
3.1 Refractive index
1.561
3.1 Flash Point
190.6°C
3.1 Precise Quality
244.12100
3.1 PSA
44.12000
3.1 logP
2.66910
3.1 Solubility
DMSO: >10?mg/mL
3.2 Appearance
White powder.
3.3 Chemical Properties
Colourless solid
3.4 Color/Form
white
3.5 pKa
pKa 4.24(H2O t=25.0) (Uncertain)
3.6 Water Solubility
DMSO: >10?mg/mL
3.7 Stability
Stable at normal temperatures and pressures.
3.8 StorageTemp
2-8°C
3. Use and Manufacturing
4.1 Definition
ChEBI: The ethyl ester of 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. It is an intravenous general anaesthetic with no analgesic activity.
4.2 General Description
Etomidate is a carboxylated imidazole intended for the inductionof general anesthesia. It is marketed as the morepotent R (+) isomer. It is believed to exert its anestheticeffect via positive modulation of the GABAA receptor. Itis not water soluble and is available in the United States as a2-mg/mL solution containing 35% v/v propylene glycol andin Europe as a soybean oil and medium-chain triglyceridesformulation. The propylene glycol has been associatedwith moderate-to-severe pain on injection and irritation ofthe vascular tissue. A high incidence of skeletal musclemovements were noted in about 32% of patients followingetomidate injection. Case reports of seizures are also foundin the literature.
4.3 GHS Classification
Signal: Warning
GHS Hazard Statements
Aggregated GHS information provided by 84 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H332 (14.29%): Harmful if inhaled [Warning Acute toxicity, inhalation]
H400 (97.62%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P261, P264, P270, P271, P273, P301+P312, P304+P312, P304+P340, P312, P330, P391, and P501
4.4 Usage
Short-time intravenous anesthetics.
4. Safety and Handling
5.1 Symbol
GHS07, GHS09
5.1 Hazard Codes
Xn
5.1 Signal Word
Warning
5.1 Risk Statements
R22
5.1 Safety Statements
S36
5.1 Packing Group
III
5.1 Hazard Class
9
5.1 Hazard Declaration
H302-H400
5.1 RIDADR
UN 3077 9 / PGIII
5.1 Caution Statement
P273
5.1 WGK Germany
3
5.1 RTECS
NI4021500
5.1 Toxicity
LD50 in mice, rats (mg/kg): 29.5, 14.8-24.3 i.v. (Janssen)
5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Hazardous to the aquatic environment, short-term (Acute) - Category Acute 1

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word

Warning

Hazard statement(s)

H302 Harmful if swallowed

H400 Very toxic to aquatic life

Precautionary statement(s)
Prevention

P264 Wash ... thoroughly after handling.

P270 Do not eat, drink or smoke when using this product.

P273 Avoid release to the environment.

Response

P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell.

P330 Rinse mouth.

P391 Collect spillage.

Storage

none

Disposal

P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

8. Precursor and Product
9. Other Information
9.0 Merck
14,3881
9.1 Target
Value
9.2 General anesthetics
Etomidate is an ultra-short effect non-barbiturate intravenous anesthetic agent allowed to be used in China , it belongs to imidazole derivatives, the appearance is white crystalline powder, melting point 115 ℃, easily soluble in water, methanol, ethanol and propylene glycol, soluble in chloroform, insoluble in acetone, insoluble in ether. Its effects on the central nervous system is similar to barbiturates. Hypnotic effect of Etomidate is strong , and its efficacy is about 12 times higher than thiopental, it has no analgesic effect. It has a rapid onset of anesthesia, after 20 seconds of intravenous injection, it produces anesthesia, anesthesia is maintained for about 5 minutes, it is quick to wake up , increasing the dose will increase the duration of action accordingly. Compared with thiopental ,its anesthesia strength is larger and it has smaller effects on the respiratory and circulatory systems. It is suitable for induction of anesthesia. Intravenous anesthesia, can increase 19% of coronary blood flow and resistance is reduced by 19%. Its obvious advantage is having no negative impact on the cardiovascular system, and it has low toxicity,it has little effect on the respiratory and circulatory system, there is a brief respiratory depression,which makes systolic blood pressure decrease slightly, and make heart rate slightly faster, compared with thiopental, above effects are less, and it has no histamine release effect. It may affect the liver and kidney function and reduce brain oxygen consumption, reduce cerebral blood flow and intracranial pressure. Clinical generally use amount is 0.1~0.4mg/kg, natural wake is 7 to 14 minutes. Distribution half-life is 2.8 minutes, and elimination half-life is 160 minutes. Hydrolyze in the liver and plasma , and the vast majority of metabolites are excreted by the kidneys. The main disadvantages of etomidate is the inhibition of adrenal cortex function, especially after long-term medication.
Induction of anesthesia: quiet, comfortable, heart rate, blood pressure are stable. The usual dose is 0.2~0.3mg/kg. Elderly, frail or critically ill patients can be reduced to 0.1~0.15mg/kg, intravenous drip.It is more suitable for cardiovascular disease, poor cardiac reserve and critically ill patients. Maintenance of intravenous anesthesia or inhalation anesthesia in short surgery or short time heart surgery : intravenous, 0.1~0.2mg/(kg · h). Outpatient minor surgery or special tests: intravenous injection, 0.2~0.3mg/kg.
After the use of the product, there will be clonic muscle contraction, using droperidol or fentanyl before anesthesia can reduce the incidence of myoclonus; if etomidate is used as inducing halothane anesthesia, the amount of halothane should be reduced .
9.3 Uses
Short-time intravenous anesthetics.
9.4 Chemical Properties
Colourless solid
9.5 Originator
Hypnomidate,Janssen,W. Germany,1977
9.6 Uses
antiestrogen
9.7 Uses
Etomidate is a hypnotic.
9.8 Uses
A GABAA receptors agonist.
9.9 Definition
ChEBI: The ethyl ester of 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. It is an intravenous general anaesthetic with no analgesic activity.
9.10 Manufacturing Process
To a mixture of 1,115 parts dl-1-phenylethylamine and 950 parts dimethylformamide are added successively 655 parts triethylamine and 1,130 parts ethyl chloroacetate. After the addition is complete, the whole is stirred overnight. Then there are added 5,600 parts anhydrous ether and the whole is filtered.
The filtrate is washed four times with water, dried and evaporated, yielding dl- N-[(ethoxycarbonyl)methyl] -1-phenylethylamine. This residue is dissolved in 4,800 parts xylene while refluxing and to this solution are added 450 parts formic acid. After boiling for a few hours, the mixture is cooled and washed successively three times with a 20% solution of formic acid, water, sodium hydrogen carbonate solution.
The organic layer is then dried, filtered and evaporated. The oily residue is distilled in vacuo, yielding 1,600 parts dl-N-formyl-N- [(ethoxycarbonyl)methyl]-1-phenylethylamine (boiling point 160°C to 170°C at 0.8 mm pressure). 30 parts of a sodium dispersion, 50% in paraffin oil are added to 450 parts tetrahydrofuran and the whole is slowly heated to a temperature of 40°C, while stirring. While maintaining this temperature (cooling on a water bath is necessary) there are added portionwise 30 parts ethanol.
After the addition is complete, the whole is cooled on an ice bath and there is added dropwise a solution of 144 parts dl-N-formyl-N- [(ethoxycarbonyl)methyl]-1-phenylethylamine in 133 parts ethyl formate. After the addition is complete, the mixture is stirred overnight at room temperature.
Then there are added 160 parts ether. After stirring for 5 minutes the mixture is poured into 1,500 parts water. The aqueous layer is separated, washed twice with 80 parts diisopropyl ether and then there are added successively 114 parts concentrated hydrochloric acid and 90 parts potassium thiocyanate in 200 parts water. The mixture is stirred for 24 hours, where upon an oil is separated.
After the addition of 750 parts water, a crystalline product is precipitated. The mixture is further stirred overnight. The solid is then filtered off and recrystallized from a mixture of ethanol and water (1:1 by volume) to yield dl- 1-(phenylethyl)-2-mercapto-5-(ethoxycarbonyl)imidazole; its melting point is 129.8°C to 130.8°C.
To a stirred mixture of 140 parts nitric acid (d = 1.37), 1 part sodium nitrate and 240 parts water are added portionwise 89 parts dl-1-(1-phenylethyl)-2- mercapto-5-(ethoxycarbonyl)imidazole. After the addition is complete, the whole is stirred for 2 hours at room temperature. The free base is liberated by addition of solid sodium carbonate and the whole is extracted with 120 parts anhydrous ether while heating. The aqueous layer is separated and extracted twice with 80 parts anhydrous ether.
The combined extracts are dried over magnesium sulfate, filtered and to the filtrate is added 2-propanol previously saturated with gaseous hydrogen chloride. The precipitated salt is filtered off, dried for 2 days at 60°C, to yield dl-1-(1-phenylethyl)-5-(ethoxycarbonyl)imidazole hydrochloride. It has a melting point 142°C to 142.8°C.
9.11 Brand name
Amidate (Hospira);Hypnomidate concentrate;Hypnomidate injection;Hypromidate;Nalgol;Sibu.
9.12 Therapeutic Function
Hypnotic
9.13 World Health Organization (WHO)
Etomidate, a potent hypnotic agent, was introduced in 1977 for use as an intravenous anaesthetic. Its prolonged use can inhibit adrenal steroidogenesis and, following reports of reduced serum cortisol levels unresponsive to ACTH injection, the manufacturer suspended promotion of etomidate for sedation in intensive care in 1983. In 1985 regulatory action taken only in the United Kingdom further restricted use of the drug to induction of anaesthesia. Etomidate remains widely available and is currently registered for induction of anaesthesia in 34 countries and for maintenance of anaesthesia in 17 countries. It has never been registered for sedation.
9.14 Biological Functions
The pharmacological properties of etomidate (Amidate) are similar to those of the barbiturates, although its use may provide a greater margin of safety because of its limited effects on the cardiovascular and respiratory systems. Since it has a relatively short elimination halflife (t1/2β = 2.9 hours), in addition to its use as an induction agent, etomidate has been used as a supplement to maintain anesthesia in some critically ill patients. Etomidate is rapidly hydrolyzed in the liver.
9.15 General Description
Etomidate is a carboxylated imidazole intended for the inductionof general anesthesia. It is marketed as the morepotent R (+) isomer. It is believed to exert its anestheticeffect via positive modulation of the GABAA receptor. Itis not water soluble and is available in the United States as a2-mg/mL solution containing 35% v/v propylene glycol andin Europe as a soybean oil and medium-chain triglyceridesformulation. The propylene glycol has been associatedwith moderate-to-severe pain on injection and irritation ofthe vascular tissue. A high incidence of skeletal musclemovements were noted in about 32% of patients followingetomidate injection. Case reports of seizures are also foundin the literature.
9.16 Biological Activity
General anesthetic with GABA modulatory and GABA-mimetic actions; selectively interacts with β 2- and β 3-subunit containing GABA A receptors. Short acting and potent hypnotic, with low toxicity.
9.17 Biochem/physiol Actions
Etomidate is a general anesthetic; potentiates GABAA transmission. The possible neuroprotective effect of etomidate against streptozotocin-induced (STZ-induced) hyperglycaemia were investigated in the rat brain and spinal cord. Etomidate treatment demonstrated neuroprotective effect on the neuronal tissue against the diabetic oxidative damage
9.18 Clinical Use
Etomidate should only beused for induction of anesthesia when the cardiac benefitsoutweigh the risks associated with adrenal insufficiency.Etomidate is quickly distributed throughout most organsin the body after intravenous administration and the tissueconcentrations equal and sometimes exceed the plasmaconcentrations. The lipid solubility of the drug allows it torapidly penetrate into the brain with peak concentrationsoccurring within 1 minute of administration. Etomidate israpidly metabolized in the plasma and liver via esterases.About 75% of the drug is eliminated in the urine as the inactiveester hydrolyzed carboxylic acid.
9.19 Side effects
Etomidate may cause pain on injection and may produce myoclonic muscle movements in approximately 40% of patients during its use as an induction anesthetic. In addition, etomidate can suppress the adrenocortical response to stress, an effect that may last up to 10 hours.
9.20 Veterinary Drugs and Treatments
Etomidate may be useful as an alternative to thiopental or propofol for anesthetic induction in small animals, particularly in patients with preexisting cardiac dysfunction, head trauma, or that are critically ill.
9.21 Metabolism
Etomidate is hydrolyzed by hepatic esterases to the corresponding inactive carboxylic acid, with subsequent renal and biliary excretion terminating its action. Its apparent elimination half-life is approximately 5 to 6 hours, with a volume of distribution of 5 to 7 L/kg. Changes in hepatic blood flow or hepatic metabolism will have only moderate effects on etomidate disposition. Concerns regarding the ability of etomidate to precipitate myoclonic jerks and inhibit adrenal steroid synthesis have been reported.
10. Computational chemical data
  • Molecular Weight: 244.294g/mol
  • Molecular Formula: C14H16N2O2
  • Compound Is Canonicalized: True
  • XLogP3-AA:
  • Exact Mass: 244.121177757
  • Monoisotopic Mass: 244.121177757
  • Complexity: 277
  • Rotatable Bond Count: 5
  • Hydrogen Bond Donor Count: 0
  • Hydrogen Bond Acceptor Count: 3
  • Topological Polar Surface Area: 44.1
  • Heavy Atom Count: 18
  • Defined Atom Stereocenter Count: 1
  • Undefined Atom Stereocenter Count: 0
  • Defined Bond Stereocenter Count: 0
  • Undefined Bond Stereocenter Count: 0
  • Isotope Atom Count: 0
  • Covalently-Bonded Unit Count: 1
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