Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor

Abstract

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 α-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.

Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-d], [3,2-d], [3,4-d] and [4,3-d]pyrimidine Derivatives

“…TAK-733 demonstrates broad activity in most melanoma cell lines and has been used to study advanced metastatic melanoma and advanced non-hematological malignancies [30][31][32]. Li et al [33] reported the development of an efficient approach to achieve TAK-733 using fewer steps and with higher yields. A polysubstituted fluoropyridone 64 was produced in one pot via a three-step cascade reaction: condensation between α-fluoromalonate and malononitrile, methyl amide formation, and intramolecular cyclization.…”

“…Li et al [ 33 ] reported the development of an efficient approach to achieve TAK-733 using fewer steps and with higher yields. A polysubstituted fluoropyridone 64 was produced in one pot via a three-step cascade reaction: condensation between α-fluoromalonate and malononitrile, methyl amide formation, and intramolecular cyclization.…”

“…Ensuing N -alkylation with the nosylate of (R)-glycerol acetonide and chlorine displacement with 2-fluoro-4-iodoaniline was successfully achieved. The final step consisted of the acid-catalyzed deprotection of the acetonide functionality to afford the pyrido[2,3- d ]pyrimidine-4,7-dione 72 ( Scheme 9 ) [ 33 ].…”

“… Synthesis of 3-[(2 R )-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methyl-3 H ,4 H ,7 H ,8 H -pyrido[2,3- d ]pyrimidine-4,7-dione ( 72 ) [ 33 ]. …”

Recent Advances in Research and Development of Fluorinated Drugs and New Methods for Fluorination, Mono-, Di-and Tri-fluoromethylation

“…值得一提的是, 鉴于 1,1-二氟-1-氯代乙酸甲酯 (MCDFA)在工业生产中大规模生产, 其成本要比使用 Ruppert 试剂降低 85%. Takeda 制药 的 Zhao 等[63] 在研发高效 MEK 抑制剂 TAK-733 的工艺 过程中就发现, 使用原来的合成方法(Scheme 36), 利用…”