The Food and Drug Administration on Wednesday approved a cancer drug
from Pharmacyclics and Janssen Biotech Inc. for a new use against a rare
blood and bone marrow disease. The agency said it approved Imbruvica
for patients with chronic lymphocytic…
LOL I remember that book being in Genentech’s bookshelves for reference! I read a bit, but couldn’t digest much from it haha. I was actually thinking about how this compound could be assembled and found a website that shows two synthetic schemes that they used in synthesizing Imbruvica. I was trying to come up with a different scheme and this is what I planned (this was merely me testing myself on planning a synthesis, no way is it more feasible than the actual routes by the companies lol):
A lot of it is based on convergent synthesis and not linear synthesis, so…it will probably be tricky to do if you attempt it. Starting from phenol and diboronic acid (expensive!), you can perform the Chan-Lam coupling to arrive at A (you’ll probably have to use phenol as LR and the other substrate in excess to ensure formation of only one aryl ether). You then take piperidin-3-ol (purchased), protect the alcohol, react it with acryloyl chloride and some inorganic base for amide formation, then deprotect the alcohol to get B. Now, you have your two pieces that are going to be eventually attached to the 1H-pyrazolo[3,4-d]pyrimidin-4-amine core (which is purchasable, but also expensive). Use NIS to functionalize the pyrazole part of the core, then Heck rxn with A, followed by Mitsunobu rxn with B to get the target compound. There may be some issues with the last step as side rxns may occur.
I know this is a really sucky scheme because it 1) is expensive, 2) is not fairly short, and 3) relies on convergent and not linear synthesis, so assembling the pieces onto the main core may or may not work in your favor. Heck, I’ve tried convergent synthesis with my project @ Genentech, and it did not go well. I ended up doing a linear synthesis instead haha.
For fragment A, you would have some difficulties with the Cham Lam as it would react at both boronic acid positions.
For fragment B, you can avoid the protecting group steps by using 10.1002/anie.201203976.