Dawn -paxalisib (GDC-0084) has been approved for rare pediatric diseases.

Recently, Kazia Therapeutics of Australia announced that the FDA has granted paxalisib (GDC-0084) the right to treat the rare pediatric disease (RPDD) of diffuse endogenetic bridge glioma (Diffuse intrinsic pontine glioma, DIPG).
DIPG is a rare and highly invasive malignant tumor in children, which lacks effective treatment and has a very high fatality rate.
Paxalisib, a small molecule inhibitor that can cross the blood-brain barrier, entered Phase II clinical trials in 2018.
February 2018, the FDA also granted paxalisib the status of orphan drug (ODD) for the treatment of glioblastoma.
, Kazia published positive interim data for paxalisib's treatment of polygonal glioblastoma (GBM) Phase II study (NCT03522298).
The study, conducted in newly diagnosed GBM patients with non-methylated MGMT initiation status, is evaluating the safety, toerability, recommended Stage II dose (RP2D), pharmacodynamics (PK) and clinical activity of paxalisib as an auxiliary therapeutic drug after receiving maximum surgical excision and combined simultaneous chemotherapy of temozolomide (TMZ).
results showed that the medium total survival (OS) of paxalisib-assisted therapy was 17.7 months, with significantly longer than the 12.7 months associated with existing standard care TMZ.
non-progressive lifetime (PFS) of paxalisib-assisted therapy was 8.5 months, longer than the 5.3 months associated with TMZ.
, patients who received the longest treatment remained disease-free 19 months after diagnosis.
, about half of the patients in the group are still receiving paxalisib treatment, and OS and PFS data are likely to improve further as research continues.
nearly two decades, newly diagnosed glioblastoma patients have not had any new medications.
above clinical data show that paxalisib is fast becoming one of the most promising drug candidates in the global pipeline of this challenging disease.
the synthesis route of the Paxalisib (GDC-0084) laboratory discovery phase is shown in Figure I.
this route starts with 2,6-chlorine-9H-rhodium 1 as the starting material, obtains intermediate 2 through selective THP protection, and then replaces it with a region selective replacement with radon 3.
then used a strong positive butyl lithium deprotone and reacted with acetone to obtain sorghum intermediate 4.
toxabenzene sulfonate deTHP to obtain amino alcohol 5.
then, intermediate 5 and 2-bromoacetate for a pro-nuclear reaction, followed by ester hydrolysing to provide glycol intermediate 6.
glycol intermediate 6 is cyclicized to obtain cycloether intermediate 7.
, the target product GDC-0084 is obtained by suzuki cross-coupled reaction under microwave conditions.
I Laboratory Discovery Phase Synthesis Route Researchers analyzed the route and concluded that( (1) if amino alcohol 5 can be achieved by directly ringing with a suitable pro-electric reagent to prepare a pyridox intermediate 7, it can shorten by 2 steps.
and it is also possible to reduce impurities 9 resulting from the elimination of reactions during the SN1 cyclification process of intermediates 6 to 7.
the over-reliance on column chromatography purification steps in the (2) route must be optimized.
(3) takes the Suzuki reaction as the last step in API synthesis, the problem of residual heavy metals in the API needs to be solved.
(4) API crystallization robustness needs to be further optimized.
the impurities involved in the Route II, the first generation of process optimization Figure III The first goal of the first generation of synthetic route process optimization is to obtain the hetero-ring intermediate 7 from the direct conversion of School Intermediate 5.
, 1,2-dYbromoethylene was determined to be the optimal reaction reagent for the cyclic reaction.
and further determine that potassium carbonate reacts as a base in a DMF solvent.
the reaction is a heating process, it is necessary to control the speed at which the material is added.
by adding substrate 5 in batches to a mixture of 1,2-bibromoethylene and potassium carbonate, it can effectively inhibit the formation of intermolete impurities and have no negative effect on conversion rate.
the criteria for the step reaction, the researchers explored the process of separation and purification of intermediate 7.
water in the mixture should not induce crystallization, but make the product oily.
extract the product into ethyl acetate and wash it with water to remove the DMF.
then exchange the ethyl acetate extract solvent for 2-propylene alcohol, which is then distilled to obtain product 7.
, the optimization condition was applied to the cyclic reaction of 5.83 Kg Sorol compound 5, and the yield of 4.27 Kg?hetero-ring 7 was obtained at a yield of 67%, and the purity of HPLC was 97.8A% (impurities 9 is 0.40A%).
four potentially genotoxic impurities (brominated ethylene, 1, 2-ddebromoethane, 9 and 10) are present in this synthesis step.
detected by developing gas chromatography, the quantitative average of these impurities in the resulting API, which is eventually separated, is 6 ppm.
, the researchers studied the Suzuki cross-coupled reaction between intermediate 7 and fangrate borate 8 in detail, optimizing the catalyst dosing and reaction solvent of the reaction.
the reaction, the reaction fluid is cooled to .lt;10oC to allow GDC-0084 to be removed from the reaction mixture, filtered to obtain the filter cake and washed with water to obtain the crude product.
using optimized reaction conditions, the Suzuki cross-coupled reaction was successfully performed using an intermediate 7 of 4.10 kg, and the resulting product can be further purified in subsequent crystallization steps.
GDC-0084 contains a large amount of residual palladium, it is necessary to add a palladium remover to reduce the metal palladium content.
careful screening, it was found that both Si-Thiol and Si-Thiourea could reduce the residual Pd to 16 ppm in the kg class experiment, while in the kg class experiment, a mixture of two scavengers was used to ensure the effective removal of Pds in different states.
at 90oC, the filter removes the sculverizer and distills the crystal from 2-propylene alcohol, eventually providing a 3.87kg GDC-0084 at an 80% yield and 99.4A% HPLC purity.
first-generation synthesis process, the researchers successfully completed the synthesis of 3.87 kg GDC-0084 to initiate clinical studies.
However, there are several aspects of the route that need to be further improved: (1) reducing the level of elimination of by-product 9 in step 1; (2) identifying a more efficient catalyst for step 2; and (3) minimizing the formation of acetylamide impurities in step 3. figure
Figure IV Second generation synthetic route Second generation process optimization In the original route, the first step of the customs reaction will produce impurities 9, and because of the use of DMF as a solvent, the reprocessing process requires solvent exchange, occupying multiple reactors for post-treatment, complicated steps.
, the researchers developed a new process for using phase transfer catalysts (PTCs) in water to synthesize intermediate 7.
reaction was 17 hours at 90oC using catalytic amounts of ammonium terabyte bromide (TBAB, 30 mol).
reaction, the product is oily and presumed from the system, which contains a large amount of 1,2-dybromoethane.
by adding ethanol, the product can be crystallization directly from the reaction mixture, and the optimal ratio of ethanol to water is 1.3:1.
the optimized reaction conditions, the intermediate 7 of 6.85 kg was obtained at the scale of 9.40 kg, with a yield of 67% and an efficient liquid chromatography purity of 98.5A, proving the robustness of the process.
the second step of the Suzuki joint reaction, the main problem is the high amount of niobium catalyst and the large total solvent volume (58 vol).
the XPhos Pd G2 as the catalyst, reducing the amount of catalyst from 2 to 0.5 mol.
using optimized reaction conditions, with intermediate 7 at 6.75 kg as the substrate, can obtain 7.49 kg of coarse GDC-0084 (94% yield, 99.4A% HPLC).
the purification process of the API, by further fine-tuning the ratio of acetic acid to water, it can be found that GDC-0084 is completely dissolved in 10 volumes of acetic acid at 90oC: water (3:1) and crystallized at 60oC.
that the temperature difference of 30oC is sufficient to complete the polish filtration process at 90oC.
Since the load of Pd in the second step is reduced from 2mol% to 0.5mol, treatment with Si-Thiol of 10wt% in this purification step is sufficient to reduce the residual Pd to less than 10ppm.
, the purification process was validated at a scale of 7.70 kg, resulting in 6.41 kg GDC-0084, HPLC purity of 99.70A and a yield of 83%.
second-generation synthesis process produced a 6.41 kg GDC-0084 in three steps at a yield of 52% and a purity of 99.70A%.
based on PMI analysis, the second generation synthesis method has improved significantly compared to the first generation synthesis method and has been shown to produce high purity API in the kg class.
Reference 1. Org. Process Res. Dev. 2016, 20, 4, 751-759. 2. ACS Med. Chem. Lett. 2016, 7, 4, 351-356.