1029044-16-3

Usage

Synthetic Routes

The synthetic routes of pexidartinib were developed by Daiichi Sankyo Company6. A novel efficient synthetic route for pexidartinib was designed via Tsuji–Trost/Heck tandem reaction in combination with palladium and silver catalysis, which avoids the need for ultra-low temperature and greatly reduces the amount of corrosive trifluoroacetic acid. The cheap and easily available materials and reagents and easy operations for workup and purification make this route more practical.

Anti-tumor Activity

Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

in vitro

plx3397 strongly dampened the systemic and local accumulation of macrophages driven by b16f10 melanomas, without affecting gr-1+ myeloid derived suppressor cells [1].

in vivo

wild-type c57 mice were orthotopically injected with gl261 cells and fed with plx3397 compound. after 2 wks, tumors in the control group showed extensive microglia infiltration. in animals fed plx3397, however, there was a substantial reduction in the number of iba1- positive cells at the tumor [2].

References

1)?DeNardo?et al.?(2011)?Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy;?Cancer Discov.?1?54 2)?Mok?et al.?(2014)?Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy;?Cancer Res.74?15 3)Sluijter?et al.?(2014)?Inhibition of CSF-1R supports T-cell mediated melanoma therapy;?PLoS One?9?e104230 4)?Peranzoni?et al.?(2018)?Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment;?Proc. Natl. Acad. Sci. USA?115?E4041 5)?Shi?et al.?(2019)?Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy;?Mol. Ther.?27?244 6) Dammeijer?et al.?(2017)?Depletion pf Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy;?Cancer Immunol. Res.?5?535

Upstream product

• 108274-33-5 5-(bromomethyl)-2-(trifluoromethyl)pyridine 
• 159451-66-8 tert-butyl N-(5-bromopyridin-2-yl)carbamate 
• 1072-97-5 5-bromo-2-pyridylamine 
• 503039-05-2 5-bromo-N-(4-methoxybenzyl)pyridin-2-amine 
• 26163-03-1 2-amino-3-bromo-5-chloropyridine 
• 823201-92-9 N-(3-bromo-5-chloro-pyridin-2-yl)-4'-methyl-benzenesulfonamide 
• 387350-39-2 1-(6-(trifluoromethyl)pyridin-3-yl)methanamine 

Relevant academic research and scientific papers

Exploratory Process Development of Pexidartinib through the Tandem Tsuji-Trost Reaction and Heck Coupling

A novel synthetic route to CSF1R inhibitor pexidartinib was designed and demonstrated. Crucial to the successful synthesis is a tandem Tsuji-Trost reaction and Heck coupling in combination with palladium and silver catalysis. The final product was obtained via five steps in 49percent yield with purity as high as 99.2percent. The cheap and available materials and reagents and easy operations for workup and purification make this route more practical.

Dealkenylative Ni-Catalyzed Cross-Coupling Enabled by Tetrazine and Photoexcitation

A new and general method to functionalize the C(sp3)-C(sp2) bond of alkyl and alkene linkages has been developed, leading to the dealkenylative generation of carbon-centered radicals that can be intercepted to undergo Ni-catalyzed C(sp3)-C(sp2) cross-coupling. This one-pot protocol leverages the easily procured alkene feedstocks for organic synthesis with excellent functional group compatibility without the need for a photoredox catalyst.

Synthetic method for continuously producing pexidartinib

The invention relates to the field of chemical synthesis, and particularly discloses a synthetic method for continuously producing pexidartinib. According to the method, 5-chloro-7-azaindole and 2-chloro-5-chloromethylpyridine are adopted as initial raw materials; an alkylation intermediate is obtained with a high yield through an alkylation reaction of the 5-chloro-7-azaindole, the intermediate does not need purification and directly and continuously participates a next-step reaction, and an amino substitution reaction on the intermediate and 3-aminomethyl-6-(trifluoromethyl) pyridine is performed to obtain a target product pexidartinib. The invention provides the synthetic route for two-step continuous production of the pexidartinib for the first time, the method is particularly suitablefor commercial mass production, and can be used for preparing the pexidartinib with low cost, high yield, high purity and high environmental protection property.

Intermediate for preparing pexidartinib, and preparation method and application thereof

The invention discloses an intermediate for preparing pexidartinib, a preparation method and application thereof. According to the invention, raw materials and reagents used in the method are cheap and easily available, the ultralow-temperature reaction and corrosive trifluoroacetic acid are successfully avoided, the method has low requirements on equipment and is beneficial to energy conservationand emission reduction, the preparation process of pexidartinib and related intermediates is simple to operate, post-treatment and purification are convenient, column chromatography is not needed, and the total yield is up to 48%; according to the method, a compound (IV) is prepared from a compound (II), a compound (V) is prepared from a compound (IV), and pexidartinib is prepared, so that the defects and deficiencies of preparation methods reported in literatures are overcome; and the intermediate for preparing pexidartinib is a compound with a structure represented by a formula (A1), a compound with a structure represented by a formula (II) or a compound with a structure represented by a formula (IV).

Simple preparation method of (by machine translation)

The invention relates to a simple preparation method, in particular to a simple preparation method of. The method utilizes N - (2 -trifluoromethyl-pyridin -5 -yl) methyl -2 - amino -5 - alkoxymethylpyridine or N - (2 - trifluoromethyl-pyridin -5 -yl) methyl -2 - amino -5 - cyanmethylpyridine (II) and acetonitrile in the presence of a base to give N - (2 -trifluoromethyl-pyridin -5 -yl) methyl -2 - amino -5 -cyanacetylmethylpyridine (III), compound III and nitromethane to prepare compound IV. The compound V, which is obtained by the addition, of 2 3 - dichloropropenal addition and base, is then subjected to hydrogenation reduction - cyclization in the presence of a catalyst to prepare the piroxicin. The method is cheap and easily available, short, simple and convenient to operate, low in waste water amount, high, green and environment-friendly, and facilitates industrial production. (by machine translation)

SYNTHESIS OF 1 H-PYRROLO[2,3-B]PYRIDIN DERIVATIVES THAT MODULATE KINASES

The present disclosure provides processes for the preparation of a compound of formula (I): or a salt thereof, active on the receptor protein kinases c-Kit and/or c-Fms and/or Flt3. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula (I).