Application of 5-fluorobenzothiazole_Kain Industrial Additive

Background and overview^[1]

5-Fluorobenzothiazole is an organic intermediate that can be prepared from 5-fluoro-2-aminothiophenol as a starting material.

Preparation^[1]

5-fluorobenzothiazole:¹H NMR (400 MHz, DMSO) δ 9.37 (s,1H), 8.26 – 8.01 (m, 2H), 7.42 (td, J = 9.0, 2.6 Hz , 1H); ¹³C NMR (100 MHz, DMSO) δ 161.59, 159.17, 156.87, 156.84, 150.40,135.46, 135.35, 124.77, 124.67, 115.38, 115.13, 10 9.30, 109.03.

Synthetic method reference: In a typical experiment, 2-aminothiophenol (0.5mmol, 0.0626g), B (C₆F₅)₃ 5mol%, 0.0128g), Et₂SiH₂ (2 mmol, 0.1764g), DMF (1mL) was put into an electromagnetic 10 mL flask with blender. The air in the reactor is replaced by CO₂. Use a balloon to maintain the CO₂ pressure at 0.1MPa. The reaction mixture was stirred at 120°C for 24 hours. Finally, the reaction mixture was cooled in ice water and the product was added. The yield was determined by H NMR spectroscopy using pyrazine as an internal standard for H NMR of the crude mixture. The pure product was separated by column chromatography and characterized by NMR.

Apply^[2]

It can be used to prepare a DYRK1 inhibitor. Such as the following compounds 5-25, 5-23. The IC50 values ​​for DYRKIA inhibition are shown in the table below.

WO2018069468 The inventors developed compounds that act as inhibitors of DYRK1A, a kinase thought to be important in neonates and early life stages. DYRK1A is a kinase whose excessive activity has recently been implicated in the pathogenesis of AD and other tauopathies, PD, and DM. The DYRK1A gene is given in triplicate to patients with Down syndrome (DS), who themselves are more susceptible to AD; 50% to 70% of DS patients develop dementia by age 60, and nearly all DS patients are over 30 All have amyloid plaques and neurofibrillary tangles.

DYRK1A is thought to play a role in the development of AD by increasing amyloid plaque formation and increasing intracellular tau protein tangles. Research has identified DYRK1A as the initiating kinase for multiple phosphorylation of tau protein, and studies of AD patient brains have shown increased expression of DYRK1A in neurons affected by tau tangles. DYRK1A was also found to directly phosphorylate the protein encoded by parkin at Ser-131, thus it inhibits the neuroprotective function of this gene. Furthermore, inhibition of DYRK1A has been found to stimulate proliferation of rodent and human beta cells in vitro and in vivo.

Main reference materials

[1] Liu Z , Gao X , Yu B , et al. Atmospheric CO2 Promoted Synthesis of N-Containing Heterocycles over B(C6F5)3 Catalyst[J]. New J. Chem. 2016:10.1039.C6NJ01721E.

[2] From PCT Int. Appl., 2018069468, 19 Apr 2018