*3.1.1.2.2 Case study 2: synthesis of pyrimidine-based Bruton's Agammaglobulinemia tyrosine kinase (BTK) [Spebrutinib, CC-292, AVL2923, (5 N-[3-[[5-fluoro-2- [4-(2-methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide] (51)*

Spebrutinib (51), an orally bioavailable, potent and selective covalent inhibitor of Bruton's agammaglobulinemia tyrosine kinase (BTK) [59]. BTK, a cytoplasmic tyrosine kinase and member of the Tec family of kinases, plays a central role in B lymphocyte development, activation, signaling, proliferation and survival [64]. Beside it potential in autoimmune related diseases, since BTK mediates the B-cell and Fc receptor signaling pathways [64], the drug is considered with great value for neoplastic disease and particularly in hematopoietic malignancies [65–68]. Upon administration, Spebrutinib targets and covalently binds to Cys 481 in BTK, blocking the ATPbinding pocket of the enzyme BTK, thereby preventing its downstream signaling. By irreversibly inhibiting BTK, administration of this agent may lead to an inhibition of B cell receptor (BCR) signaling and may inhibit cell proliferation of B-cell malignancies. Readers interested in a wider and deeper perceptions on BTK inhibitors and embodied role in malignant and non-malignant disease are referred to excellent reviews [65–68].

Synthetically, the molecule (49) is produced starting from 2,4-dichloro-5 fluoropyrimide (45). The coupling of the two different substituents to the pyrimidine core was performed under classical conditions. The first step was accomplished by reacting the 2,4-dichloro-5-fluoropyrimide with the mono-BOCylated *meta*diaminobenzene (46). The selective displacement of chloride at C4 by *tert*-butyl N-(3 aminophenyl) carbamate (46) renders high ratio of regioselective synthon and yielded the intermediate (47), which was reacted with the second substrate at C2 by 4-(2 methoxyethoxy)aniline (48). Due to the presence of *tert*-BOC (acid cleavable) as protecting group the two steps have be conducted under basic conditions.

Following the cleavage of the protecting group *tert*-BOC under acidic conditions, the acryloyl chloride (prop-2-enoyl chloride) was coupled to the free amine under basic conditions (**Figure 6**).
