1. Effect of Temperature on Crisaborole Formation .
| Process
Parameter |
Area % in HPLC |
||||
|---|---|---|---|---|---|
| Temperature (°C) | 10 | 13 | 14 | 15 | Crisaborole (6) |
| 0 | 0.01 | 9.8 | 3.2 | 14.34 | 72.0 |
| –20 | 0.01 | 8.2 | 2.4 | 8.25 | 81.10 |
| –50 | 0.01 | 6.99 | 1.00 | 3.24 | 87.45 |
| –60 | 0.01 | 6.26 | 0.80 | 2.81 | 89.39 |
| –70 | 0.01 | 6.20 | 0.80 | 2.81 | 89.25 |
a
All reactions were conducted using 5.0 g (1.0 equiv) of compound 10, n-butyllithium (2.0 equiv), and triisopropyl borate (4.0 equiv), with a residence time of 1.5 s. The temperature was varied as detailed in the accompanying table for the coupling reaction. Following this, cyclization was carried out using 3 M HCl (7.0 equiv). The area percentage under the peak at 210 nm was determined using high-performance liquid chromatography (HPLC) to assess the product formation and impurity levels.