What is 6-amino-2,2-dimethyl-4H-pyrido[3,2-b] [1,4] oxazin-3-one?

6-amino-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one is the key intermediate of Fostamatinib, which is a medication approved by the U.S. Food and Drug Administration since 2018 for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib is administered orally as a disodium hexahydrate salt and is a prodrug of the active compound tamatinib (R-406) [1], which is a competitive spleen tyrosine kinase (Syk) inhibitor for ATP binding.

Spleen tyrosine kinase (Syk) is a non-receptor cytoplasmic enzyme that is primarily expressed in cells of hematopoietic lineage. Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors, including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes, including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development and plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens.  

As the synthesis intermediate of Fostamatinib, which is the first marketed Syk kinase inhibitor, 6-amino-2,2-dimethyl-4H-pyrido[3,2-b] [1,4]oxazin-3-one is very important, especially in how to improve its synthesis process.

Scheme 1 Synthesis of 6-amino-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one

Scheme 1 shows the synthesis route of 6-amino-2,2-dimethyl-4H-pyrido[3,2-b] [1,4] oxazin-3-one. Specifically, 2- methyl-2 -((2- nitropyridine -3-) oxygen) propionate ethyl ester (product in step I) was obtained by nucleophilic substitution reaction with 3-hydroxy-2-nitropyridine as raw material, and then reduced cyclization was used to obtain 6-amino-2,2-dimethyl-4H-pyrido[3,2-b] [1,4] oxazin-3-one. The preparation process has easily-​available raw materials, low cost, easy industrialization, high synthesis yield and high product purity.

Victor and his coworkers synthesized 2,2-Dimethyl-6-{[4-(4-hydroxy-3,5-dimethoxyphenylamino) pyrimidin4-yl] amino}-2H-pyrid[3,2-b] [1,4] oxazin-3(4H)-one (dMe-MT-SYK-03), which is intermediate of Fostamatinib. In the synthesis, 6-amino-2,2-dimethyl-4H-pyrido[3,2-b] [1,4] oxazin-3-one act as raw material and prepare dMe-MT-SYK-03 with two steps.

The synthesis is shown in scheme 2. The first step is the synthesis of 6-[(6-Chloropyrimidin-4-yl) amino]-2,2-dimethyl-2H-pyrid[3,2-b]- [1,4] oxazin-3(4H)-one. 2,4-Dichloro-1,3,5-triazine was dissolved in dry degaussed DMF, and 6-Amino-2,2-dimethyl-2H-pyrid[3,2-b] [1,4] oxazin-3-(4H)-one was added, then the reaction mixture was stirred at 60 °C for 8 h under inert atmosphere. The solvent was evaporated at 5 Torr. The residue was washed with water and separated by chromatography eluting with chloroform/methanol mixture of increasing polarity. The standard workup procedure afforded the title product. The second step is the preparation of dMe-MT-SYK-03. The above compound, obtained in the first step, was dissolved in dry degaussed DMF. 4-Hydroxy-2,6-dimethoxyaniline was added, and the mixture was stirred at 100 °C for 20 h under inert atmosphere. The solvent was evaporated at 5 Torr. The residue was washed with water and separated by chromatography eluting with chloroform/methanol mixture of increasing polarity, finally, the target product was obtained.

                      Scheme 2 Synthesis of compound dMe-MT-SYK-03

References

[1] Xu, Yungen etc., Process for preparation of Fostamatinib key intermediate, CN 109912622

[2] Victor S. Stroylov, etc., Modeling comparative selectivity profiles of kinase inhibitors using FEP/MD protocol, Mendeleev Commun., 2017, 27, 349–351