1867-66-9 Usage
Description
Ketamine hydrochloride, also known as Ketalar, is an off-white solid that is formulated as an acidic solution with a pH range of 3.5 to 5.5. It is available with or without 0.1 mg/mL benzethonium chloride preservative and is marketed as a racemic mixture. Ketamine is a rapid-acting agent that does not act at the GABAA receptor but instead acts as a noncompetitive antagonist at the glutamate, NMDA receptor, and an unspecific ion channel receptor. It is used as a veterinary anesthetic and is classified as a class A drug in the UK.
Uses
Used in Anesthesia:
Ketamine hydrochloride is used as an anesthetic agent for induction, as the sole agent for general anesthesia, or in combination with other agents. It is particularly effective due to its rapid onset and unique mechanism of action, which involves blocking the flow of calcium ions into the cell, thus preventing excitatory synaptic transmissions in the brain and spinal cord.
Used as a Controlled Substance (Depressant):
Ketamine hydrochloride is used as a depressant and is classified as a controlled substance. Its ability to induce a state of dissociation and sedation makes it useful in certain medical and veterinary applications, although it is also known for its illicit use as a club drug.
Used in Pharmaceutical Industry:
Ketamine hydrochloride is used as an active pharmaceutical ingredient in the development of various medications, primarily for its anesthetic and sedative properties. Its unique mechanism of action and rapid onset make it a valuable component in the pharmaceutical industry.
Used in Veterinary Medicine:
Ketamine hydrochloride is used as a veterinary anesthetic, providing rapid and effective anesthesia for animals during surgical procedures or other medical interventions. Its safety and efficacy in veterinary medicine make it a popular choice for veterinarians.
Originator
Ketanest,Parke Davis,W. Germany,1969
Manufacturing Process
The 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine used as an
intermediate is prepared as follows. To the Grignard reagent prepared from
119.0 g of cyclopentyl bromide and 19.4 g of magnesium is added 55.2 g of
o-chlorobenzonitrile. The reaction mixture is stirred for 3 days and thereafter
hydrolyzed in the usual manner. From the hydrolysis there is obtained ochlorophenylcyclopentylketone, BP 96° to 97°C (0.3 mm), nD251.5452. To
21.0 g of the ketone is added 10.0 g of bromine in 80 ml of carbon
tetrachloride.1-Bromocyclopentyl-(o-chlorophenyl)-ketone, BP 111° to 114°C (0.1 mm) is
isolated in the usual manner. Since it is unstable, it must be used
immediately. The bromoketone (29.0 g) is dissolved in 50 ml of liquid
methylamine. After one hour, the excess liquid methylamine is allowed to
evaporate. The organic residue is dissolved in pentane, and upon evaporation
of the solvent, 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine,
MP 62°C, is isolated.1-Hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine (2.0 g) is
dissolved in 15 ml of Decalin and refluxed for 2,5 hours. After evaporation of
the Decalin under reduced pressure, the residue is extracted with dilute
hydrochloric acid, the solution treated with decolorizing charcoal, and the
resulting acidic solution is made basic. The liberated product, 2-methylamino-
2-(o-chlorophenyl)-cyclohexanone, after crystallization from pentane-ether,
has MP 92° to 93°C. The hydrochloride of this compound has MP 262° to
263°C.
Therapeutic Function
Anesthetic
Biological Functions
Ketamine is a cyclohexanone derivative whose pharmacological
actions are quite different from those of the
other IV anesthetics. The state of unconsciousness it
produces is trancelike (i.e., eyes may remain open until
deep anesthesia is obtained) and cataleptic; it has frequently
been characterized as dissociative (i.e., the patient
may appear awake and reactive but does not respond
to sensory stimuli). The term dissociative
anesthesia is used to describe these qualities of profound
analgesia, amnesia, and superficial level of sleep.
Biological Activity
Non-competitive NMDA receptor antagonist (EC 50 values are 13.6 and 17.6 μ M for NR1/NR2A and NR1/NR2B subunit combinations respectively). Dissociative anesthetic.
Biochem/physiol Actions
Selective NMDA glutamate receptor antagonist; veterinary anesthetic.
Pharmacology
Slow IV administration of ketamine does not cause
gradual loss of airway reflexes, apnea, or general muscular
relaxation.The onset of the ketamine-induced “anesthetic
state” is accompanied by a gradual, mild increase
in muscle tone (which greatly resembles catatonia), continued
maintenance of pharyngeal and laryngeal reflexes,
and opening of the eyes (usually accompanied by
nystagmus). Although reflexes may be maintained, the
airway still must be protected, since ketamine sensitizes
laryngeal and pharyngeal muscles to mucous or foreign
substances, and laryngospasm may occur.
Ketamine also can be contrasted to other intravenous
drugs in its ability to cause cardiovascular stimulation
rather than depression. The observed increases
in heart rate and blood pressure appear to be mediated
through stimulation of the sympathetic nervous system.
In a healthy, normovolemic, unpremedicated patient,
the initial induction dose of ketamine maintains or stimulates
cardiovascular function. In contrast, patients with poor cardiac reserve, compromised autonomic control,
or hypovolemia may undergo a precipitous fall in blood
pressure after induction of anesthesia with ketamine. If
selection of the patient and preoperative preparation
are carefully done, however, ketamine may be an excellent
drug for the induction of anesthesia in individuals
who cannot tolerate compromise of their cardiovascular
system.
The analgesia induced by ketamine also is a property
that separates it from other IV anesthetic drugs.
Analgesia is obtained without a deep level of anesthesia.
When subdissociative doses of ketamine are given
either IV or intramuscularly (IM), they provide adequate
analgesia for postoperative pain relief as well as
analgesia for brief operations on the skin, such as debridement
of third-degree burns. Because it can be regarded
as a nearly complete anesthetic (hypnosis and
analgesia), does not require anesthesia equipment, and
is relatively protective of hemodynamics, ketamine also
can be very useful outside of normal operating room
conditions, such as may be found during painful radiographic
procedures.
A most important advantage of ketamine over other
anesthetic agents is its potential for administration by
the IM route.This is particularly useful in anesthetizing
children, since anesthesia can be induced relatively
quickly in a child who resists an inhalation induction or
the insertion of an IV line. Ketamine has a limited but
useful role as an IM induction agent and in pediatrics.
Clinical Use
Like other dissociative anesthetics, ketamine isabused for its hallucinatory effects. Most of the illegallyused ketamine comes from stolen legitimate sources, particularlyfrom veterinary clinics or smuggled in fromMexico.Ketamine is metabolized via N-demethylation to formthe main metabolite norketamine. Norketamine has aboutone third the potency of the parent compound. Minor metabolicpathways include hydroxylation of the cyclohexanonering; hydroxylation followed by glucuronide conjugation,and hydroxylation followed by dehydration to the cyclohexenonederivative.
Side effects
The most serious disadvantage to the use of ketamine is
its propensity to evoke excitatory and hallucinatory
phenomena as the patient emerges from anesthesia.
Patients in the recovery period may be agitated, scream
and cry, hallucinate, or experience vivid dreams. These
episodes may be controlled to some extent by maintaining
a quiet reassuring atmosphere in which the patient
can awaken or if necessary by administering tranquilizing
doses of diazepam.
Other reported side effects include vomiting, salivation,
lacrimation, shivering, skin rash, and an interaction
with thyroid preparations that may lead to hypertension
and tachycardia. Ketamine also may raise intracranial
pressure and elevate pulmonary vascular resistance, especially
in children with trauma or congenital heart disease.
Increases in intraocular pressure also may occur,
and vigilance is required if ketamine is used in ocular
surgery.
Safety Profile
Poison by
intramuscular, intraperitoneal, and
intravenous routes. Moderately toxic by
ingestion. Human systemic effects by
intravenous and possibly other routes:
analgesia, coma, hallucinations and distorted
perceptions, dyspnea. An experimental
teratogen. An anesthetic. When heated to
decomposition it emits very toxic fumes of
Cland NOx.
Drug interactions
Molecular weight (daltons) 274.2 (as
hydrochloride)
% Protein binding 20-50
% Excreted unchanged in urine 2 (88% as
metabolites)
Volume of distribution (L/kg) 4
Half-life - normal/ESRF (hrs) 2-4 / Unchanged
Metabolism
After intravenous boluses, ketamine shows a bi- or
triexponential pattern of elimination. The alpha phase
which lasts about 45 minutes, represents ketamine's
anaesthetic action, and is terminated by redistribution
from the CNS to peripheral tissues and hepatic
biotransformation to an active metabolite norketamine.
Other metabolic pathways include hydroxylation of the
cyclohexone ring and conjugation with glucuronic acid.
Ketamine is excreted mainly in the urine as metabolites.
Check Digit Verification of cas no
The CAS Registry Mumber 1867-66-9 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 1,8,6 and 7 respectively; the second part has 2 digits, 6 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 1867-66:
(6*1)+(5*8)+(4*6)+(3*7)+(2*6)+(1*6)=109
109 % 10 = 9
So 1867-66-9 is a valid CAS Registry Number.
InChI:InChI=1/C13H16ClNO.ClH/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14;/h2-3,6-7,15H,4-5,8-9H2,1H3;1H
1867-66-9Relevant articles and documents
Process Research and Impurity Control Strategy of Esketamine
Gao, Shenghua,Gao, Xuezhi,Yang, Zhezhou,Zhang, Fuli
, p. 555 - 566 (2020/05/19)
An improved synthesis of (S)-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the (S)-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity. The ICH-grade quality (S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.
Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions
Kassin, Victor-Emmanuel H.,Gérardy, Romaric,Toupy, Thomas,Collin, DIégo,Salvadeo, Elena,Toussaint, Fran?ois,Van Hecke, Kristof,Monbaliu, Jean-Christophe M.
, p. 2952 - 2966 (2019/06/18)
A robust three-step continuous flow procedure is presented for the efficient and sustainable preparation of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous flow processing, starts from commercially available chemicals, utilizes low toxicity reagents and a FDA class 3 solvent under intensified conditions. The procedure features a unique hydroxylation step with molecular oxygen, a fast imination relying on triisopropyl borate and a thermolysis employing Montmorillonite K10 as a heterogeneous catalyst, all three steps being performed in ethanol. The three individual steps can be run independently or can be concatenated, thus providing a compact yet efficient setup for the production of ketamine. The scalability of the critical hydroxylation step was assessed in a commercial pilot continuous flow reactor. The process can also be adapted for the preparation of ketamine analogs. A thorough computational study on the backbone rearrangement of the cyclopentylphenylketone scaffold under thermal stress rationalizes the experimental selectivity and the various experimental observations reported herein.
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