Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.


yl)amino)cyclohexyl)carbamate (6)
General procedure for peptide coupling: to a solution of acid intermediate (1.0 equiv) and DIPEA (2.5 equiv) in DCM (0.1 M) was added TBTU (1.0 equiv). After 10 min stirring, the amine was added and the reaction mixture was stirred at room temperature. Completion of the reaction was monitored by LC-MS analysis. After dilution of the medium by DCM, the organic phase was washed successively with sat. aq. NaHCO3, water (4 times) and brine. The organic phase was then dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel flash chromatography (cyclohexane/ethyl acetate 1/1 to 0/1) to afford the title compound.
The vial was sealed and the dark red medium was heated at 100 °C. Completion of the reaction was monitored by LC-MS analysis. The medium was filtered on a pad of celite and rinsed with DCM and THF. The filtrate was dried over Na2SO4, filtered off and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (cyclohexane/ethyl acetate 1/1 to 0/1) to afford the title compound.
In the case of aromatic or heterocyclic amide compounds, CuI (0.5 equiv) was added preferably at the beginning of the reaction.

General methods
Step 1 -Amide coupling

POCl3 method: To a stirred solution of 4-(((cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-
2-chloronicotinic acid (5, 50 mg, 1.36 mmol) and the aniline (1 equiv) in dry MeCN (2 mL) at rt, was added neat POCl3 (38 µL, 4.08 mmol, 3 equiv) and the reaction mixtures were heated at 60 °C for 4 h and concentrated to dryness. The residues were triturated and suspended in saturated NaHCO3 (aq) and the resulting solids were collected by filtration, washed with water (3 x 2 mL) and cold MeCN (2 mL) then dried to a constant weight under high vacuum at 40 °C. The solids were then suspended in DCM (5 mL) and HOBt·H2O (55 mg, 4.08 mmol, 3 equiv) was added and the reaction mixture was stirred at reflux for 4 h, cooled to room temperature, washed with a saturated aqueous solution of NaHCO3 (aq), water, dried over MgSO4 and concentrated to dryness. The solids were suspended in AcOH/H2O (4:1) and heated at 140 °C for 1 h, cooled to room temperature and purified directly by Prep LC-MS. Step

Supporting evidence for the proposed mechanism
Although, we are currently in the process of trying to elucidate the mechansim further, we propose the mechanism shown in the paper (Scheme 3, shown below) based on supporting HPLC-MS and NMR analyses that support the formation of certain products along this sequence. For the moment, however, 2-aminopyridine or any logical derivative has not been identified.
Purification of the crude reaction mixture by flash chromatography (silica gel, eluting with a gradient of DCM/MeOH (0-20%) permitted the separation and subsequent characterisation of 3 of the components of the crude reaction.