CEP-32496 (free base)

Base Information

• Chemical Name: CEP-32496 (free base)
• CAS No.: 1188910-76-0
• Molecular Formula: C24H22F3N5O5
• Molecular Weight: 517.464
• Mol file: 1188910-76-0.mol

Synonyms:CEP 32496;CEP32496;

Chemical Property of CEP-32496 (free base)

Chemical Property:

• PSA: 127.35000
• LogP: 5.34670
• Solubility.: ≥25.85 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH

Purity/Quality:

98%,99%, ^*data from raw suppliers

CEP32496 ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: B-Raf is a MAP kinase kinase kinase, which functions downstream of Ras family GTPases to activate MEK1/2 and ERK1/2 signaling. Mutations of B-Raf, particularly at Val600, are common in melanomas and melanocytic nevi. CEP-32496 is a potent inhibitor of B-RafV600E (Kd = 14 nM in an in vitro binding assay). It blocks B-RafV600E-dependent phosphorylation of MEK in human melanoma A375 and colorectal cancer COLO 205 cells (IC50s = 78 and 60 nM, respectively). CEP-32496 binds kinases other than B-Raf but displays selective cytotoxicity for cells expressing B-RafV600E. It displays good oral bioavailability in rats, dogs, and monkeys and has single oral dose pharmacodynamics inhibition of both pMEK and pERK in B-RafV600E colon carcinoma xenografts in nude mice.
• Uses: CEP 32496 is an orally active BRAFV600E inhibitor with selective cellular and in vivo antitumor activity.

Technology Process of CEP-32496 (free base)

There total 8 articles about CEP-32496 (free base) 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: 96.0%

3-(6,7-dimethoxyquinazolin-4-yloxy)-benzenamine (1188908-37-3) + phenyl (5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)carbamate (1188911-77-4) → CEP-32496 (1188910-76-0)

Guidance literature:

With dmap; In Isopropyl acetate; at 70 ℃; for 9h; Inert atmosphere;

Reference yield: 75.0%

3-(6,7-dimethoxyquinazolin-4-yloxy)-benzenamine (1188908-37-3) + 4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (1188911-75-2) → CEP-32496 (1188910-76-0)

Guidance literature:

With dmap; In tetrahydrofuran; at 20 - 45 ℃; for 39h;

DOI:10.1021/jm2009925

Reference yield:

3,3,3-trifluoro-2,2-dimethylpropanoic acid (889940-13-0) → CEP-32496 (1188910-76-0)

Guidance literature:

Multi-step reaction with 5 steps

1.1: diethyl ether; dichloromethane / 68 h / 0 - 20 °C

2.1: sodium hydride / tetrahydrofuran; mineral oil / 15.75 h / 70 - 75 °C

3.1: sodium hydrogencarbonate; hydroxylamine sulfate / methanol; water / 15 h / 65 °C

3.2: 0.08 h / 140 °C / 5250.53 Torr

4.1: potassium carbonate / tetrahydrofuran / 18.5 h / 20 °C

5.1: dmap / tetrahydrofuran / 39 h / 20 - 45 °C

With dmap; sodium hydride; sodium hydrogencarbonate; potassium carbonate; hydroxylamine sulfate; In tetrahydrofuran; methanol; diethyl ether; dichloromethane; water; mineral oil;

DOI:10.1021/jm2009925

upstream raw materials:

3,3,3-trifluoro-2,2-dimethylpropanoic acid

3-(6,7-dimethoxyquinazolin-4-yloxy)-benzenamine

4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate

methyl 3,3,3-trifluoro-2,2-dimethylpropanoate

Downstream raw materials:

1-[3-(6,7-dimethoxy-quinazolin-4-yloxy)-phenyl]-3-[5-(2,2,2-trifluoro-1,1-dimethylethyl)isoxazol-3-yl]urea hydrochloride

Refernces

• 1、 Rowbottom, Martin W.,Faraoni, Raffaella,Chao, Qi,Campbell, Brian T.,Lai, Andiliy G.,Setti, Eduardo,Ezawa, Maiko,Sprankle, Kelly G.,Abraham, Sunny,Tran, Lan,Struss, Brian,Gibney, Michael,Armstrong, Robert C.,Gunawardane, Ruwanthi N.,Nepomuceno, Ronald R.,Valenta, Ianina,Hua, Helen,Gardner, Michael F.,Cramer, Merryl D.,Gitnick, Dana,Insko, Darren E.,Apuy, Julius L.,Jones-Bolin, Susan,Ghose, Arup K.,Herbertz, Torsten,Ator, Mark A.,Dorsey, Bruce D.,Ruggeri, Bruce,Williams, Michael,Bhagwat, Shripad,James, Joyce,Holladay, Mark W.. "Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1, 1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E". . p. 1082 - 1105. Retrieved 2012/04/04.