135729-61-2

Basic information

• Product Name: Palonosetron
• Synonyms: Palonosetron [inn];Rs 25233-197;(S)-2-((S)-quinuclidin-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one;Palonosetron;(S-(R*,R*))-2-(1-Azabicyclo(2.2.2)oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz(de)isoquinolin-1-one;1H-Benz(de)isoquinolin-1-one, 2-(1-azabicyclo(2.2.2)oct-3-yl)-2,3,3A,4,5,6-hexahydro-, (S-(R*,R*))-;2-(1-Azabicyclo(2.2.2)oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz(de)isoquinolin-1-one;2-Qhbiqo
• CAS NO: 135729-61-2
• Molecular Formula: C19H24N2O
• Molecular Weight: 296.40666
• EINECS: 1312995-182-4
• Mol File: 135729-61-2.mol
• Article Data: 9

Chemical Properties

• Melting Point: 87-88°
• Boiling Point: 470.414 °C at 760 mmHg
• Flash Point: 209.529 °C
• Appearance: /
• Density: 1.242 g/cm³
• PKA: 9.77±0.33(Predicted)
• CAS DataBase Reference: Palonosetron(CAS DataBase Reference)
• NIST Chemistry Reference: Palonosetron(135729-61-2)
• EPA Substance Registry System: Palonosetron(135729-61-2)

Safety Data

• Hazardous Substances Data: 135729-61-2(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Palonosetron is used as an antiemetic agent for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It works by blocking the serotonin 5-HT3 receptors in the brain, which are responsible for triggering the vomiting reflex during chemotherapy. This helps to alleviate the discomfort and distress associated with CINV, improving the overall quality of life for cancer patients undergoing chemotherapy.
Used in Drug Combinations:
Palonosetron is also used in combination with netupitant (under the trade name Akynzeo) to treat nausea and vomiting in patients undergoing cancer chemotherapy. This combination therapy aims to provide more effective control of CINV, as netupitant is a neurokinin-1 receptor antagonist that works synergistically with Palonosetron to prevent the onset of vomiting.

Clinical Use

Anti-emetic: For use with cancer chemotherapy

Synthesis

(S)-3-Aminoquinuclidine was condensed with inexpensive 1,8-naphthalic anhydride (138) to furnish imide 139 in 93% yield and isolated as its TFA salt. Imide 139 was hydrogenated at 5 psi to give intermediate 140 with one of the reduced aromatic ring. The less hindered C-3 carbonyl group in 140 was selectively reduced to a hydroxy group by using sodium borohydride in ethanol under nitrogen at low temperature to give intermediate 141. Intermediate 141 was not isolated because of the formation of a tight boron complex. Subsequently, acid was added to 141 in i-PrOH to decompose the boron complex and dehydrate intermediate 141 to 142, which was conveniently isolated as its HCl salt in 75% yield from 139. Palonosetron (XVIII) was obtained in 57% yield by palladium-catalyzed hydrogenation of 142.

Enzyme inhibitor

This serotonin 5-HT3 receptor antagonist and longlasting anti-emetic (FW = 296.41 g/mol; CAS 135729-61-2), known by code name RS 25259, RS 25259-197, trade name Aloxi?, and systematic name (3aS)-2-[(3S)-1- azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin- 1-one, is used to treat chemotherapy-induced nausea/vomiting. Polonosetron affects both peripheral and central nervous systems, reducing vagus nerve activity, thereby deactivating the 5-HT3 receptor-dense vomiting center located in the medulla oblongata. It is without effect on dopamine receptors or muscarinic receptors. Primary Mode of Inhibitor Action: Intravenously administered palonosetron has a linear pharmacokinetic profile, with a long terminal elimination half-life of ~40 hours and moderate (62%) plasma protein binding. Its high affinity and long half-life most likely explains its persistent antiemetic effect. Similar 5- HT3 antagonists include tropisetron, ondansetron, dolasetron, and granisetron. The effectiveness of each depends on particular variants of 5- HT3 receptors expressed by the patient, including changes in promoters for the receptor genes

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

Palonosetron is eliminated by a dual route, about 40% eliminated through the kidney and approximately 50% metabolised by CYP2D6, and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes in the liver to form two primary metabolites, which have less than 1% of the 5HT3 receptor antagonist activity of palonosetron. After a single intravenous dose of [14C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with unchanged palonosetron representing approximately 40% of the administered dose.

InChI:InChI=1/C19H24N2O/c22-19-16-6-2-4-14-3-1-5-15(18(14)16)11-21(19)17-12-20-9-7-13(17)8-10-20/h2,4,6,13,15,17H,1,3,5,7-12H2/t15-,17+/m0/s1

Upstream product

• 135729-56-5 (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one 
• 135729-55-4 (S)-2-<1-azabicyclo<2.2.2>oct-3-yl>-2,4,5,6-tetrahydro-1-oxo-1H-benzisoquinoline hydrochloride 
• 135755-51-0 palonosetron hydrochloride 
• 135729-57-6 2-<(R)-1-azabicyclo<2.2.2>oct-3-yl>-1,2,4,5-tetrahydro-1H-benzisoquinolin-1-one 
• 135729-78-1 N-<(S)-1-azabicyclo<2.2.2>oct-3-yl>-5,6,7,8-tetrahydronaphthalene-1-carboxamide 
• 110808-69-0 5,6,7,8-tetrahydronaphthylene-1-carboxylic acid chloride 
• 4242-18-6 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid 
• 177793-80-5 C₁₈H₂₆N₂ 
• 85977-52-2 (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid 
• 177793-79-2 N-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalene-1S-carboxamide 
• 135729-55-4 palonosetron hydrochloride 

Downstream Products

• 135755-51-0 palonosetron hydrochloride 
• 135755-51-0 palonosetron hydrochloride 
• 813425-83-1 Palonosetron N-oxide 

Relevant articles and documents

A hydrochloric acid palonosetron production method

The invention belongs to the field of organic synthesis, and particularly relates to a production method of high-purity and high-yield palonosetron hydrochloride. Chiral compounds, namely, (S)-(-)-1,2,3,4-tetrahedro-naphthoic acid and S-3-aminoquinuclidine, are taken as raw materials, and an intermediate is obtained; the intermediate has a reduction reaction in the presence of NaBH4 and BF3*CH3OH, a product is added to a hydrochloric acid aqueous solution for a reflux reaction after the reaction, and a transparent oily substance is obtained through extraction after the reflux reaction; toluene is added to the substance, a toluene solution of triphosgene is dropwise added again at the temperature ranging from 10 DEG C to 15 DEG C, white solids are separated out, a reaction is performed under the condition of heating reflux, and the toluene solution of the triphosgene is dropwise added again under the reflux condition; then a system is cooled to the temperature ranging from 10 DEG C to 15 DEG C, BF3*CH3OH is added, the system is added to water and the hydrochloric acid aqueous solution at the reflux temperature after addition, then a reflux reaction is performed at the heating reflux temperature, and then a crude product is obtained through washing, extraction and crystallization; the crude product is dissolved in acetone, repeated crystallization is performed after dissolution, and the refined palonosetron hydrochloride is obtained. Steps are simple and convenient, reaction conditions are mild, and the production method is easy to operate and suitable for industrial production.

Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging

Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (Ki = 0.26 ± 0.05 nM) similar to the parent drug (Ki = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-11C)-N-granisetron ([11C]2) through N-alkylation with [11C]CH3I, respectively. Both compounds [18F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [11C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [18F]15 and [11C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT3 receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3 receptors in vivo.

Process for the Preparation of Substantially Pure Palonosetron and its Acid Salts

This invention relates to an improved and scalable process for the preparation of substantially pure palonosetron and its acid addition salts, in particular hydrochloride (I) which comprises of, (a) converting intermediate (IIa) as such or as its freebase (II) to a crude mixture of diastereomeric palonosetrons (VIII) or (VIIIa) contaminated with varying amounts of unconverted intermediate (II) or (IIa) via hydrogenation under pressure with an appropriately chosen hydrogenation catalyst in an suitable organic solvent.(b) making the resulting crude mixture of diastereomeric palonosetrons (VIII) or (VIIIa) contaminated with varying amounts of unconverted intermediate (II) or (IIa) substantially free from (II) or (IIa) via halogenation reaction.(c) Finally, converting the resulting diastereomeric palonosetron (VIII) or its hydrochloride (VIIIa) substantially free from intermediate (II) or (IIa) to the desired palonosetron hydrochloride (I) in substantially pure form via selective crystallization from a suitable single or mixture of organic solvents.

PROCESSES FOR THE PREPARATION OF PALONOSETRON

The present invention relates to novel processes for the preparation of N-[(3S)-1- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of Formula I. The present invention further relates to processes for the preparation of palonosetron or its salts thereof using N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I as an intermediate.

HIGH PURITY PALONOSETRON BASE AND ITS SOLID STATE CHARACTERISTICS

The present invention describes the process for the preparation of pure enantiomeric form of palonosetron base of formula (I), and its solid-state characteristics of said compound.

NOVEL CRYSTALLINE FORMS OF PALONOSETRON HYDROCHLORIDE

The present invention relates to novel crystalline forms, designated as Form (I) and Form (II) of Palonosetron Hydrochloride ((3as)-2[(3s)-1-Azabicyclo[2.2.2]Oct-3-yl]-2,3,3a,4,5,6- hexahydro-1H-benz[de]isoquinoline-1-one mono hydrchloride) and processes for their preparation. Palonosetron Hydrochloride is useful as anti-emetic agent during the chemotherapy of treatment of cancer patients. It is marketed globally under the brand names 'Aloxi' and 'Onicit'.

PALONOSETRON FREE BASE AND PROCESS FOR ITS PREPARATION

The present invention provides novel palonosetron free base in an amorphous form and crystalline form-G and processes for their preparation. The present invention also provides a process for the preparation of palonosetron hydrochloride from the novel palonosetron free base in an amorphous form and/or in crystalline form-G.

Total synthesis of the 5-HT3 receptor antagonist palonosetron

A short and efficient synthetic route to the 5-HT3 receptor antagonists 1 and 2 (palonosetron) was developed. The novel adjustment of the oxidation states at the necessary centers of imide 7 was accomplished by hydrogenation, selective sodium borohydride reduction, and dehydration to yield 1. The sodium borohydride reduction of imide 8 was selective for the C-3 carbonyl versus the C-1 carbonyl next to the aromatic ring to give the hydroxy compound 9. It was essential to keep the sodium borohydride reduction free of oxygen, or diols 10a and 10b were formed as significant byproducts.

2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series,2-(quinuclidin-3-yl)tetrahydropyrido[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridge