99614-02-5

Hazards Identification

Pictogram(s):

Signal:

Danger

GHS Hazard Statements:

H301 (87.5%): Toxic if swallowed [Danger Acute toxicity, oral]
H315 (68.75%): Causes skin irritation [Warning Skin corrosion/irritation]
H319 (75%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (68.75%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]
H362 (62.5%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]
H400 (81.25%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]
H410 (81.25%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes:

P203, P260, P261, P263, P264, P264+P265, P270, P271, P273, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501

Hazard Classes and Categories:

Acute Tox. 3 (87.5%)
Skin Irrit. 2 (68.75%)
Eye Irrit. 2 (75%)
STOT SE 3 (68.75%)
Lact. (62.5%)
Aquatic Acute 1 (81.25%)
Aquatic Chronic 1 (81.25%)

Usage

Uses

Used in Pharmaceutical Industry:
Ondansetron is used as an antiemetic agent for the prevention and treatment of nausea and vomiting caused by various conditions such as chemotherapy, radiation therapy, and surgery. It helps to control the symptoms by blocking the action of serotonin, a neurotransmitter that can trigger vomiting.
Used in Research and Forensic Applications:
Ondansetron is used as a certified reference material in research and forensic applications. It serves as a standard for the development, validation, and quality control of analytical methods and procedures related to the detection and quantification of ondansetron in biological samples.
Used in Alcoholism Treatment:
Ondansetron is used as a therapeutic agent for reducing alcohol consumption and mood disturbances in early-onset alcoholics. It has been found to be effective in reducing the desire to drink alcohol and improving mood-related symptoms in individuals with alcohol use disorder.

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.

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

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

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

Upstream product

• 693-98-1 2-methylimidazole 
• 99614-64-9 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one 
• 27387-31-1 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 
• 1630-73-5 N-ethyloxazolidine 
• 20073-50-1 2-(oxazolidin-3-yl)ethanol 
• 51200-87-4 4,4-dimethyl-oxazolidine 
• 99614-01-4 Ondansetron hydrochloride 
• 108-74-7 1,3,5-trimethyl-1,3,5-triazacyclohexane 
• 51-80-9 bis-(dimethylamino)methane 
• 880-09-1 di(N-piperidinyl)methane 
• 132659-89-3 3-[(dimethylamine)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride 
• 294863-10-8 ethyl 3-(1-methyl-1H-indol-2-yl)propanoate 
• 88221-09-4 ethyl 3-(1-methyl-1H-indol-2-yl)acrylate 
• 27421-51-8 1-methyl-1H-indole-2-carboxaldehyde 

Downstream Products

• 99614-01-4 Ondansetron hydrochloride 
• 99614-64-9 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one 
• 153139-56-1 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one 

Relevant academic research and scientific papers

C(sp2)-H Bond Multiple Functionalization in Air for Construction of Tetrahydrocarbazoles with Continuous Quaternary Carbons and Polycyclic Diversification

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.

IMIDAZOLYL MODULATORS OF 5-HT3 RECEPTORS

The present invention relates to new imidazolyl modulators of 5-HT3 receptors, pharmaceutical compositions thereof, and methods of use thereof.

Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one and ondansetron therefrom

The present invention provides a rapid, high-yielding process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one without using a secondary amine as a catalyst, and without using glacial acetic acid as a solvent. The present invention further provides a rapid, high-yielding process for preparing ondansetron from 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one without using alumina as a catalyst.

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

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

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]- 4H-carbazol-4-one or its salt is prepared in high yield by reacting a compound of formula 2 with a compound of formula 3 and a compound of formula 4 in the presence of an acid, an alkylsilylhalide compound or an acylhalide compound, in an solvent, and thus, such an inventive process can be favorably applied to a large-scale mass production thereof.

NEW POLYMORPHIC FORMS OF ONDANSETRON, PROCESSES FOR PREPARING THEM, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE AS ANTIEMETICS

This invention relates to new polymorphs of (±)1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-il)methyl]-4H-carbazol-4-one, known under the INN of ondansetron, to processes for preparing said polymorphs, to pharmaceutical compositions containing them and to their use in the treatment and prophylaxis of nausea and vomiting. The invention provides new stable polymorphic forms of ondansetron and processes for manufacturing them at an industrial scale.

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

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.

NOVEL PROCESS FOR THE PREPARATION OF IMIDAZOLYL COMPOUNDS

The present invention relates to a method for the preparation of an imidazolyl compound of the general formula (I), wherein: Ra and Rb each separately are (C1-C6)alkyl, (C1-C6)alkoxyalkyl, optionally substituted aryl or heteroaryl; or wherein Ra and Rb together form a further homocyclic or heterocyclic system comprising one or more rings; Ra’ and Rb’ each are hydrogen or together form a carbon-carbon double bond, said carbon-carbon double bond optionally being part of an aromatic system; Rc is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1,-C6)alkoxyalkyl or halogen; Rd is hydrogen or (C1-C4)aIkyl; Re is hydrogen or (C1-C4)aIkyl; m is 1 or 2; and R1, is hydrogen or (C1-C4)aIkyl; as well as its acid addition salt;characterized in that a compound of the general formula (II) is reacted with a compound of the formula (III), wherein: R is a hydrogen, a (C1-C4)alkyl group optionally substituted with a hydroxygroup or an optionally substituted aryl group, R', R", R'" and R"" each individually are a hydrogen or a (C1-C4)aIkyl group; followed by a reaction with a compound of the formula (IV), wherein R1, Rd and Re have the meanings defined above; and optionally followed by a reaction with a suitable acid. De method according to the present invention is especially useful for the preparation of ondansetron and cilansetron.

ONDANSETRON FORMS AND PROCESSES OF MAKING THE SAME

The invention relates to a solid crystalline ondansetron having at least one of the following characteristics: a melting endotherm peak greater than or equal to 240°C; a trace amount of a base or residue thereof comprising an alkali metal, an amine, an ammonium or an ion thereof; or a water content of 1.3 to 1.5 wt%, and to a composition comprising same and a pharmaceutically acceptable excipient, and to a process, which comprises: neutralizing an acid addition salt of ondansetron to liberate ondansetron free base; and precipitating said ondansetron free base from a liquid media, and to a process, which comprises dissolving ondansetron free base in a solvent and precipitating said dissolved ondansetron free base to form ondansetron having a melting endotherm peak of greater than or equal to 240°C measured on DSC at 5°C/min.

PROCESS FOR PREPARING 1,2,3,9-TETRAHYDRO-9-METHYL-3-[(2-METHYL-1H-IMIDAZOL-1-YL)METHYL]-4H-CARBAZOL-4-ONE

A process for preparing ondansetron by transamination of an ondansetron structural analog that can be readily prepared conveniently by a Mannich reaction is provided. The process represents an improvement upon known procedures for making ondansetron by transamination because of its rapid rate, selectivity and the ease with which the product can be isolated from the reaction mixture.