99614-02-5 Usage
Abstract
Ondansetron is used to prevent nausea and vomiting that may be caused by surgery, cancer chemotherapy, or radiation treatment. The 5-HT3 receptor antagonists in Ondansetron are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting and radiotherapy-induced nausea and vomiting, through blocking the actions of chemicals in the body.
The efficacy is better than metoclopramide while less sedating than cyclizine or droperidol. However, it has little effect on vomiting caused by motion sickness. It can be given by mouth, by injection into a muscle or into a vein.
Mechanism of action
Ondansetron and granisetron, dolasetron are three common clinically used antiemetics, ondansetron is an effective serotonin (5-HT3) receptor blocker which is reversible and selective,? for α1, α2, β1, β2-adrenergic receptors and the histamine H1, H2 receptors ,it has the minimal effect ,for H receptors, central and peripheral dopaminergic receptors ,it has no antagonistic effect ,it can suppress the chemotherapy and radiotherapy-induced nausea and vomiting. Compared with metoclopramide, its antiemetic effect is stronger and it has no extrapyramidal reactions. For vomiting induced by cisplatin, cyclophosphamide, doxorubicin, etc. it can produce rapid and strong antiemetic effect. It is suitable not only for the treatment of nausea and vomiting caused by the cytotoxic chemotherapy and radiation therapy, but also for the prevention and treatment of nausea and vomiting induced by surgeries.
Ondansetron works as a transit point between the visceral afferent nerve activated in the gastrointestinal tract and vomiting center within the spinal cord , which leads to the diaphragm and abdominal muscles movements. Chemotherapy and radiation therapy can cause intestinal 5-HT release and cause vagus nerve stimulation by 5-HT3 receptor ,which causes vomiting reflex. This product blocks this reflex occurring ,at the same time it blocks the vomiting triggered by the central action. The mechanism about postoperative nausea and vomiting? is unknown. Ondansetron in combination with dexamethasonecan can enhance the anti-emetic effect.
Chemical properties
It is crystallized from methanol, mp 231-232 ℃.
Ondansetron hydrochloride dihydrate : C18H19N3O·ClH·2H2O[99614-01-4]. From the water-isopropanol ,? white crystalline solid is generated, mp 178.5~179.5 ℃.
Ondansetron Hydrochloride Monohydrate: C18H19N3O·HCl·H2O. Crystallization, melting point? 186~187 ℃.
3S-type: [α] D25-14 ° (C = 0.19, methanol).
3R-type: [α] D24 + 16 ° (C = 0.34, methanol).
Application
As serotonin (5-HT3) receptor antagonists, it belongs to efficient antiemetic drugs,it has high strength and high selectivity, and it can control the receptor stimulation caused vomiting in the small intestine and CTZ (chemoreceptor trigger zone).It is used for treatment of chemotherapy and radiotherapy-induced emesis ,in particular ,it is used for the treatments of the emetic effect caused by cisplatin, dacarbazine, mechlorethamine, doxorubicin . It has no extrapyramidal effects ,and it can be used in conjunction with acetylcholine,its antiemetic effect is better than Metoclopramiden, Dompesidone, phenothiazines and butyrophenones.
Preparation
First preparation method:
After the reaction of 2-bromo-aniline and 1,3-cyclohexanedione,use? dehydrobromination cyclization to produce the tetrahydrocarbazole derivative, and then react with polyformaldehyde and dimethylamine, then introduce dimethylaminomethyl in position 2 , the compound (ⅲ) is obtained. 3.80g compound (Ⅲ) reacts with methyl iodide, methyl group is introduced at position 9 while the side-chain amino is quaternized ,to give 5.72g compound (Ⅳ). 2.0g compound (Ⅳ) and 2-methyl-1H-imidazole in dimethyl formamide, stir and react at 95 ℃, to give 0.60g ondansetron.
Second preparation method:
cyclohexanone reacts with phenylhydrazine to give tetrahydrocarbazole in 85% yield. This is dissolved in tetrahydrofuran and water, under nitrogen,it is added dropwise the? tetrahydrofuran solution of 2,3,5,6-tetrachloro-1,4-benzoquinone at 0℃, stir to give the oxidation product (Ⅱ), in a yield of 67.4% .
Compound (Ⅱ), ethanol, concentrated hydrochloric acid, paraformaldehyde and dimethylamine hydrochloride,are refluxing together. After Process, then in acetone, concentrated hydrochloric acid is added ,then stir at 50℃ to give methylation product (the V), in a yield of 71.7%.
Compound (V) and 2-methylimidazole in water,react at 110 ℃ reaction, the compound (Ⅵ)is generated, in a yield of 70.9%.
Compound (Ⅵ), methyl iodide and potassium carbonate, are stirred at room temperature until solid disappears . Pour it into water, stir , filter , wash? with water and recrystallize from methanol to give ondansetron,in a yield of 57.2%. It is dissolved in a mixture of acetone and water, concentrated hydrochloric acid is added ,after the reaction , ondansetron hydrochloride dihydrate can be obtained? , the yield is 92.6%
Third preparation method:
Compound (II), potassium carbonate, acetone and dimethyl sulfate, are stirred at room temperature. Compound (Ⅶ)is generated , the yield is 91%.
Compound (Ⅶ) is dissolved in ethanol ,at reflux ,there is the batch addition of a mixture of paraformaldehyde and dimethylamine hydrochloride.After the addition is finished, reflux. After treatment, the compound (Ⅷ)is obtained, the yield is 67%.
(Ⅷ) is dissolved in ethanol, inlet hydrogen chloride gas, obtaining its hydrochloride. The hydrochloride is added to water, 2-Methylimidazole is added at 50 ℃ , reflux to obtain ondansetron,the yield is 70%. This is dissolved in isopropyl alcohol, water and concentrated hydrochloric acid, and it is stirred at room temperature to obtain ondansetron hydrochloride dihydrate, the yield is 90.5%.
References
https://en.wikipedia.org
https://www.drugs.com/ondansetron.html
Description
Ondansetron (hydrochloride) (CRM) (Item No. 21710) is a certified reference material categorized as an antiemetic. Formulations containing ondansetron have been used to reduce alcohol consumption and mood disturbances in early-onset alcoholics. This product is intended for research and forensic applications.
Originator
Ondansetron hydrochloride ,Chemo Iberica , Spain
Indications
Ondansetron (Zofran) is potent antagonists of 5-HT3 receptors,which is found peripherally
on vagal nerve terminals and centrally in the
CTZ. During chemotherapy that induces vomiting, mucosal
enterochromaffin cells in the GI tract release serotonin,
which stimulates 5-HT3 receptors.
Clinical Use
Ondansetron
Side effects
This causes vagal
afferent discharge, inducing vomiting. In binding to
5-HT3 receptors, ondansetron blocks
serotonin stimulation, hence vomiting, after emetogenic
stimuli such as cisplatin. Headache is the most frequently
reported adverse effect of these medications.
Safety Profile
A poison by intravenous route.Human systemic effects by intravenous route: jaundice.When heated to decomposition it emits toxic vapors ofNOx.
Veterinary Drugs and Treatments
Used as an antiemetic when conventional antiemetics are ineffective,
such as when administering cisplatin or for other causes of
intractable vomiting. The use of ondansetron in cats is somewhat
controversial and some state it should not be used in this species.
Drug interactions
Potentially hazardous interactions with other drugs
Cytotoxics: possible increased risk of ventricular
arrhythmias with panobinostat and vandetanib.
Dopaminergics: possible increased risk of
hypotension with apomorphine - avoid.
Metabolism
Ondansetron is metabolised in the liver through multiple
enzymatic pathways; it is a substrate for cytochrome
P450 isoenzymes, primarily CYP3A4, but also CYP1A2
and CYP2D6. The metabolites do not contribute to the
pharmacological activity of ondansetron. Less than 5% of
a dose is excreted unchanged in the urine
Check Digit Verification of cas no
The CAS Registry Mumber 99614-02-5 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 9,9,6,1 and 4 respectively; the second part has 2 digits, 0 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 99614-02:
(7*9)+(6*9)+(5*6)+(4*1)+(3*4)+(2*0)+(1*2)=165
165 % 10 = 5
So 99614-02-5 is a valid CAS Registry Number.
InChI:InChI=1/C17H18N4O/c1-12-18-8-10-20(12)11-21-9-7-15-16(17(21)22)13-5-3-4-6-14(13)19(15)2/h3-6,8,10H,7,9,11H2,1-2H3
99614-02-5Relevant articles and documents
C(sp2)-H Bond Multiple Functionalization in Air for Construction of Tetrahydrocarbazoles with Continuous Quaternary Carbons and Polycyclic Diversification
Dong, Suzhen,Jia, Shikun,Liu, Shunying,Ni, Dan,Pi, Rou,Song, Longlong,Tang, Jie,Yang, Fan
, (2020/03/04)
The C(sp2)-H function of indole ketone with diazo compound via a rhodium(II)-catalyzed intramolecular electrophilic trapping reaction under mild conditions in air was demonstrated. The established methodology provided a highly efficient approach for direct synthesis of mutisubstituted tetrahydrocarbazoles with continuous quaternary carbons. The resulting products facilitate further modification to conveniently construct tetrahydrocarbazoles with additional fused heterocyclic rings. By phenotypic screening, several products exhibit good anticancer bioctivities in osteosarcoma cell lines.
A ONE-POT PROCESS FOR THE PREPARATION OF ANTIEMETIC AGENT, 1,2,3,9-TETRAHYDRO-9-METHYL-3[(2-METHYL)-1H-IMIDAZOLE-1-YL)METHYL]-4H-CARBAZOL-4-O
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Page/Page column 18-19, (2008/06/13)
A one-pot industrial process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazole-1-yl)methyl]-4H-carbazol-4-one of Formula-(I) from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of Formula-(IV) involves reaction of Formula (IV) with HNR1R2 salt and paraformaldehyde, where R1,R2 are independently alkyl groups or together forms a cyclic alkyl group, in a solvent system of acetic acid and hydrocarbon solvent to form a crude mixture of intermediate compounds of Formula (III) and (VIII), which is converted to ondansetron (Formula (I)) without isolation by reaction with 2-methyimidazole in a suitable solvent system in the same pot.
PROCESS FOR PREPARING 1,2,3,9-TETRAHYDRO-9-METHYL-3-[(2-METHYL-1H-IMIDAZOLE-1-YL)METHYL]-4H-CARBAZOL-4-ONE OR ITS SALT
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Page/Page column 14-15, (2008/06/13)
The present invention provides an improved process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or its salt, which is useful as an anti-vomiting agent, in a high yield under a mild condition, so as to be favorably applied to a large-scale mass production thereof.
