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

Organic Process Research and Development

Volumn 16, Issue 10, 2012, Pages 1652-1659

  Zhao, Yuxin ^a   Zhu, Lei ^b   Provencal, David P ^a   Miller, Todd A ^a   O'Bryan, Colin ^a   Langston, Marianne ^b   Shen, Ming ^b   Bailey, Dan ^b   Sha, Dezhi ^c   Palmer, Travis ^c   Ho, Thuy ^c   Li, Mai ^c  

^a Takeda San Diego Inc   (United States)

^b MILLENNIUM PHARMACEUTICALS INC   (United States)

^c IRIX Pharmaceuticals Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVE PHARMACEUTICAL INGREDIENTS; AMIDE FORMATION; CASCADE REACTIONS; CONTROLLED CRYSTALLIZATION; DEPROTECTION; HIGH YIELD; HYDROXYL FUNCTIONALITY; INTRAMOLECULAR CYCLIZATIONS; KINASE INHIBITORS; MALONONITRILES; N-ALKYLATION; ONE POT;

AMIDES; CHLORINE; CYCLIZATION; FORMIC ACID;

GLYCEROL;

EID: 84870864044     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op300198a     Document Type: Article

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25. LC/MS and MS/MS analyses indicated that this impurity is either the N-methylated or O-methylated pyridopyrimidone core. The mechanism of this byproduct formation is still not clear.
26. Preliminary LC/MS analysis showed that these two impurities contained the same molecular weight (twice as the mass of desired product 20) and fragmentation pattern; thus, they could be the diastereo-dimers of the product.
27. On gram-scale synthesis, Form H.was usually observed as the single polymorph form isolated directly from reaction mixture. Upon scale-up (a few hundred grams scale), the mixture of amorphous solid and Form H.was observed.