Netupitant

Base Information

• Chemical Name: Netupitant
• CAS No.: 290297-26-6
• Molecular Formula: C30H32 F6 N4 O
• Molecular Weight: 578.601
• UNII: 7732P08TIR
• DSSTox Substance ID: DTXSID50183271
• Nikkaji Number: J2.298.344J
• Wikipedia: Netupitant
• Wikidata: Q19598139
• NCI Thesaurus Code: C96745
• RXCUI: 1552337
• Pharos Ligand ID: 6LMXFPUU1DUH
• Metabolomics Workbench ID: 152108
• ChEMBL ID: CHEMBL206253
• Mol file: 290297-26-6.mol

Synonyms:2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl)propanamide;2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-methylpropanamide;benzeneacetamide, N, alpha, alpha-trimethyl-N-(4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl)-3,5-bis(trifluoromethyl)-;benzeneacetamide, N, alpha,alpha-trimethyl-N-(4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl)-3,5-bis(trifluoromethyl)-, hydrochloride (1:2);netupitant;netupitant dihydrochloride;netupitant hydrochloride;RO 67-3189 000;RO 673189000;RO-67-3189;RO-67-3189 000;RO-673189000

Chemical Property of Netupitant

Chemical Property:

• Vapor Pressure: 3.09E-14mmHg at 25°C
• Melting Point: 156.2-160.0 °C
• Boiling Point: 597.4°C at 760 mmHg
• PKA: 7.89±0.38(Predicted)
• Flash Point: 315.1°C
• PSA: 39.68000
• Density: 1.255
• LogP: 6.78990
• Storage Temp.: 2-8°C
• Solubility.: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• XLogP3: 6.8
• Hydrogen Bond Donor Count: 0
• Hydrogen Bond Acceptor Count: 10
• Rotatable Bond Count: 5
• Exact Mass: 578.24803063
• Heavy Atom Count: 41
• Complexity: 865

Purity/Quality:

98% ^*data from raw suppliers

Netupitant ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC1=CC=CC=C1C2=CC(=NC=C2N(C)C(=O)C(C)(C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)N4CCN(CC4)C
• Recent ClinicalTrials: Netupitant and Palonosetron Hydrochloride in Preventing Chronic Nausea and Vomiting in Patients With Cancer
• Recent EU Clinical Trials: MyRisk: Efficacy and safety evaluation of oral Akynzeo? in patients receiving MEC at high risk of developing CINV based on a prediction tool. A multinational and multicenter study.
• Recent NIPH Clinical Trials: None
• Description: Netupitant, originally developed by Helsinn Healthcare and later licensed to Eisai, Inc., was approved in the USA in October 2014 for the treatment of chemotherapy-induced nausea and emesis. Akynzeo ? is a fixed-dose combination of the new drug netupitant and the previously-approved 5-HT3 antagonist palonosetron. While palonosetron obtained approval previously for treating nausea and emesis occurring within the first 24 hours (acute phase) after chemotherapy, netupitant provides a synergistic effect with palonosetron, assisting in prevention of nausea and emesis in later stages following chemotherapy (25–120 h after chemotherapy treatment). Several clinical trials showed that this combination of netupitant and palonosetron (Akynzeo ?), in comparison to treatment with palonosetron treatment alone, led to an improved percentage of patients in all phases who did not experience any nausea and emesis after undergoing chemotherapy. Netupitant itself joins the class of selective Neurokinin- 1 (NK1) receptor antagonists which, in addition to their use for treating chemotherapy-induced nausea and emesis, also play an important role as therapies for depression and anxiety. Netupitant is an insurmountable antagonist of the neurokinin-1 (NK1) receptor (Ki = 0.95 nM in CHO cells expressing the human recombinant receptor). It is selective for human NK1 over human NK2 and NK3 and rat NK1 (Kis = >1,500 nM) and over 50 G protein-coupled receptors, monoamine transporters, and ion channels when used in the nanomolar range. Netupitant decreases the maximal response to substance P-induced contractions in isolated guinea pig ileum with long-lasting effects. It also dose-dependently inhibits the substance P-induced scratching, biting, and licking response in mice when used at doses ranging from 1-10 mg/kg and decreases NK agonist-induced foot tapping in gerbils (ID50s = 1.5 mg/kg, i.p., or 0.5 mg/kg, oral). Formulations containing netupitant have been used in the treatment of chemotherapy-induced nausea and vomiting.
• Uses: Netupitant is a potent and selective neurokinin-1 receptor (NK1) receptor antagonist. It is achiral and orally active.

Technology Process of Netupitant

There total 46 articles about Netupitant which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 81.0%

methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine (290297-25-5) + 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (289686-69-7) → netupitant (290297-26-6)

Guidance literature:

With sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 35 - 40 ℃; for 3h; Cooling with ice;

Reference yield: 80.0%

1-methyl-piperazine (109-01-3) + 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide (401891-55-2) → netupitant (290297-26-6)

Guidance literature:

With potassium carbonate; In dichloromethane; at 80 ℃; for 3h;

Reference yield:

[6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl]carbamic acid methyl ester (342417-02-1) → netupitant (290297-26-6)

Guidance literature:

Multi-step reaction with 2 steps

1: Red-Al / toluene; CH₂Cl₂ / 1 h / 50 °C

2: 13.5 g / i-Pr₂NEt / CH₂Cl₂ / 3 h / 0 °C

With N-ethyl-N,N-diisopropylamine; sodium bis(2-methoxyethoxy)aluminium dihydride; In dichloromethane; toluene;

DOI:10.1021/jo0523666

upstream raw materials:

methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine

2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride

1-methyl-piperazine

6-chloro-4-(o-tolyl)nicotinamide

Downstream raw materials:

4-(5-{2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamido}-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-{[bis(tert-butoxy)phosphoryl]oxymethyl}piperazin-1-ium

4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium

1-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-4-methylpiperazine 1,4-dioxide

Refernces

• 1、 -. "Netupitant free alkali crystal form A and preparation method thereof". Paragraph 0025; 0026. . Retrieved 2017/07/22.
• 2、 -. "SUBSTITUTED 4-PHENYL-PYRIDINES FOR TREATMENT OF NK-1 RECEPTOR RELATED DISEASES". Paragraph 0160-0162. . Retrieved 2018/10/31.