Follow SiliCycle on Facebook Follow SiliCycle on Twitter Follow SiliCycle on LinkedIn Watch our videos on Youtube

Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084

> back to SiliaMetS Case Studies

GDC-0084 is a potent and selective dual inhibitor of PI3K/mTOR with the ability to penetrate the blood−brain barrier, as it was discovered in Genentech laboratories (Roche group) for the treatment of various brain cancers. Highlights of the synthesis include a phase transfer catalyzed annulation in water, and the last step of the API is the Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a palladium catalyst.

In this cross-coupling reaction, an initial catalyst screen found PdCl2(dppf)•CH2Cl2 to be superior to PdCl2(PPh3)2, PdCl2(AmPhos), and Pd(OAc)2/SPhos in terms of conversion. A brief solvent screen (entries 4-7) using 2 mol % catalyst showed that aqueous THF was the better system, affording more than 98% conversion after 2 h (scheme).

The crude GDC-0084 contained a large amount of residual palladium (≈ 2400 ppm) were exposed to a variety of scavengers (20 wt % loading) in an effort to reduce the level of metal. Both Si-thiol and Si-thiourea were found to lower the residual Pd the most efficiently (figure).

The main issues in the stage 2 process were the high catalyst loading (2 mol %, PdCl2(dppf)•CH2Cl2) for the Suzuki coupling and the large total solvent volume (58 vol). The optimized Suzuki cross-coupling was successfully demonstrated to provide 7.49 kg of crude GDC-0084 (94 % yield). Overall, replacing PdCl2(dppf)•CH2Cl2 with Buchwald’s second generation XPhos Pd G2 catalyst enabled the catalyst loading to be lowered from 2 to 0.5 mol %, and the scavenging procedure to be limited to one single SiliaMetS Si-Thiol (instead of both Si-Thiol and Si-Thiourea), and only 10 wt % was sufficient to lower residual Pd to below 10 ppm.

Stumpf, A. et al. Org. Process Res. Dev., 2016, 20, 751 - 759

 

Read more

2 Item(s)

Set Descending Direction
per page

List  Grid 

  1. SiliaMetS Thiol (SH) (R51030B)

    SiliaMetS Thiol (SH) (R51030B)

    Our most versatile and robust metal scavenger for a variety of metals under a wide range of conditions.
  2. SiliaMetS Thiourea (THU) (R69530B)

    SiliaMetS Thiourea (THU) (R69530B)

    SiliaMetS Thiourea (Si-THU) is a versatile metal scavenger for all forms of palladium and is widely used in the pharmaceutical industry. It works particularly well in organic solvents. It can also be used to scavenge Ag, Pt, Ru, Rh and Hg. Once complexed with a transition metal, it has been reported as being an effective catalyst.

2 Item(s)

Set Descending Direction
per page

List  Grid