Momolotinib is an oral Janus kinase (JAK1/JAK2) and activator AChemicalbook receptor type 1 (ACVR1) inhibitor discovered by Cytopia Research and developed by GlaxoSmithKline (GSK). It was approved by the US FDA in September 2023 and became the first and only targeted drug for the treatment of myelofibrosis patients with anemia.
Molotinib inhibits abnormal signaling by competitively binding to the ATP sites of JAK1/JAK2, while targeting ACVR1 to regulate hepcidin levels and improve anemia symptoms. Clinical studies have shown that Momotinib significantly reduces transfusion dependence, enables patients to achieve transfusion independence, and has good long-term treatment tolerance without the risk of chronic toxicity accumulation. Compared to other JAK inhibitors such as Luketinib, its unique dual mechanism breaks through the limitations of traditional therapies that only alleviate splenomegaly or symptoms, providing an innovative choice for patients with myelofibrosis complicated by anemia, combining disease correction and anemia improvement.
Molotinib, molecular formula: C23H22N6O2, molecular weight: 414.46.
Molotinib CAS: 1056634-68-4
The chemical name is N - (cyanomethyl) -4- (2- ((4-methylphenyl) amino) pyrimidin-4-yl) benzamide.
Route 1:
Step 1: Suzuki coupling catalyzed by tetratriphenylphosphine palladium with a yield of 60%
Step 2: Acid catalyzed SNAr reaction, ester base hydrolysis, two-step yield of 88%
Step 3: Amidation reaction of carboxylic acid with aminoacetonitrile, yield 88%
Route 2:
Step 1: Under acidic conditions, aniline reacts with cyanamide to obtain guanidine structure with a yield of 78%
Step 2: Introduce vinyldimethylamine into the carbonyl alpha position using DMF-DMA, with a yield of 82%
Step 3: The guanidine structure and vinyldimethylamine are heated in acetonitrile to form pyrimidine nuclei, followed by ester hydrolysis, resulting in a two-step yield of 78%
Step 4: The final step of amidation reaction is the same as route 1, with a yield of 87%
Reference:
[1] Burns, C. J.; Spencer, A.; Monaghan, K. A. Multiple myeloma treatment. WO 2012149602 A1, 2012.
[2] Zhu, C.; Xue, X.; Han, G.; Mao, Y.; Xu, J. New and practical synthesis of Momelotinib. J. Heterocycl. Chem. 2017, 54, 2902−2905.
<Reprinted from: https://mp.weixin.qq.com/s/4UVEzK8FCrVgLfN8xKTvjQ>
