1035556-25-2

Upstream product

• 100-39-0 benzyl bromide 
• 1035556-24-1 3-benzyl-5-chloro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 369-35-7 2-fluoro-4-nitroaniline 
• 1035556-22-9 3-benzyl-6-(methylamino)pyrimidin-4(3H)-one 
• 1035556-23-0 3-benzyl-5-hydroxy-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 29632-74-4 2-fluro-4-iodoaniline 

Downstream Products

• 1286748-45-5 C₂₁H₁₅F₂IN₄O₂ 
• 1035556-43-4 5-(2-fluoro-4-iodophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-51-1 (R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-50-0 (S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-83-9 3-(2-(dimethylamino)ethyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1286747-87-2 C₁₇H₁₅ClFIN₄O₄ 
• 1035555-63-5 TAK-733 
• 1035555-65-7 (R)-5-(4-bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-67-9 (R)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-64-6 (S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-62-4 6-fluoro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-88-4 3-benzyl-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035556-27-4 5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035556-44-5 C₁₄H₁₀BrFN₄O₂ 

Relevant academic research and scientific papers

Process research and kilogram synthesis of an investigational, potent MEK inhibitor

TAK-733 (1) is an investigational, novel MEK kinase inhibitor that bears a 6-fluoropyridopyrimidone core. Process research of 1 was conducted, and an efficient, scalable route was developed. The key intermediate, a multisubstituted fluoropyridone, was formed in one pot via a three-step cascade reaction: condensation between a-fluoromalonate and malononitrile, methyl amide formation, and intramolecular cyclization. Chlorination of the hydroxyl functionality and cyclization with formic acid provided the desired pyridopyrimidone core in high yield. Subsequent N-alkylation with the nosylate of (R)-glycerol acetonide and displacement of the chlorine with 2-fluoro-4-iodoaniline proceeded successfully with good yields. Final acid-catalyzed deprotection of the acetonide functionality followed by a controlled crystallization protocol afforded the active pharmaceutical ingredient (API) with the desired polymorph. Compared to the initial synthesis, this route was more concise (six steps compared to the original nine steps), and the overall yield was improved significantly (from 3% to 25%). These improvements allowed for production of multikilograms of 1.

Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment.

MAPK/ERK KINASE INHIBITORS

Compounds of the following formula are provided for use with MEK (I): wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.