The new TGF beta R1 inhibitor BMS-986260 kg class was developed.

At present, TGF beta R1 inhibitors have become a popular research direction for cancer treatment drugs, and a number of TGF beta R1 inhibitors have entered clinical studies, including Lilly's Galunisertib, LY3200882 and South Korean biotech company Vactosertib, which offer new hope for the treatment of non-small cell lung cancer (NSCLC), bowel cancer (CC), and pancreatic cancer (PC).
BMS-986260 (Figure 1) is a new TGF beta R1 inhibitor developed by BMS, which shows great prospect of cancer drug development, and BMS's process developers have been working on the large-scale synthesis process development of the molecule in order to meet preclinical and clinical needs.
Figure I BMS-986260 structural BMS-986260 the initial pharmaceutical synthesis process shows in Figure II, the synthesis process is based on 2-brominated quine-3-amine 2, first in DMF-DMA condensation to obtain amine compound 3; compound 3 and bromine acetylene in alkaline conditions to obtain ringing reaction to obtain intermediate 4; intermediate 4 and sanbutyl (intermediate 4 and sanbutyl) Vinyl) tin in the Pd catalyst under the still conjugate reaction to obtain the intermediate 5; intermediate sneeze 5 by tetraoxygenation cut off to obtain aldehyde-based compound 6; compound 6 and ethanolamine coup to obtain amine compound 7; and finally Ya'an compound 7 and intermediate 10 in alkaline conditions to form the mite ring (Vanuse Lenmizole synthesis) to obtain the target product 1 (BMS-986260).
Figure II BMS-986260 pharmaceutical izede synthesis route wherein, intermediate 10 is obtained by aldehyde-based compound 8 by two-step reaction (Figure 2).
the above-mentioned pharmaceutical synthesis route can get a small amount of BMS-986260, can meet the pre-pharmaceutical assessment needs, but to meet the pre-clinical and clinical needs, a lot of optimization work must be done, mainly related to: a. In the process of synthesizing a large number of products (APIs), it is necessary to avoid the use of tin tin and tetraoxygenated radon and other toxic reagents; b. intermediate 10 of the synthesis yield is low, need further optimization; c. pharmaceutical synthesis route heavy, most intermediates are purified by column chromatography, not suitable for large-scale synthesis.
, BMS researchers redeveloped the process.
BMS researchers first redeveloped the synthesis of key intermediatealdehyde 6. The reverse synthesis analysis of
intermediate aldehyde 6 is shown in figure III, Route A design is made of ester 11 synthetic aldehyde 6; ester 11 is condensed by compound 12 and bromide acetylene cyclication; and compound 12 is obtained by acid 13 by esterification reaction.
Route A design is made of amine compound 14 synthetic aldehyde 6; compound 14 can be converted by compound 15 through the methyl's kinetic group; compound 15 can be condensed by the pyrethroid compound 16 and bromide acetylene cyclic.
the reverse synthesis analysis of intermediate aldehyde 6, according to the reverse synthesis analysis, the researchers began to explore the specific process.
, Route A was required to use 120-degree high temperature conditions due to the harsh ness of intermediate 12 synthesis conditions, and no further research and development was carried out.
researchers turned to route B for system development. the forward synthesis route of Route 12 in figure 4
figure 4 Is route B is shown in Figure V, with compound 16 as the raw material, including steps such as shrinking with DMF-DMA, ringing with brominated acetylene, further shrinking with DMF-DMA, oxidation cut-off, etc.
the researchers optimized the route step by step.
The synthesis of the intermediate 10 was also optimized by the researchers after a step-by-step optimization of the forward synthesis route of Route B in figure 5 Route B. The second-generation synthesis route obtained
optimized is shown in Figure 6.
figure six BMS-986260 second generation synthesis process optimized BMS-986260 to 6-methylpyrethine-3-amine 16 as raw material, first with DMF-DMA shrink to obtain intermediate 19; The inline reaction was obtained by the amine intermediate 14, the step of which the researchers obtained the best alkali-DBU by screening, the intermediate 14 by high iodide oxidation cut-off to obtain the key intermediate 6, the intermediate 6 and ethanolamine condensed to form aamine compound 7, and finally, compound 7 and compound 10 re-alkaline conditions to form a mymlyn ring, that is, the target product BMS-986260.
the improved BMS-986260 synthesis process, successfully avoided the use of ethylene (three-butyl) tin, tetraoxygenated tantaum and other high-risk reagents, improve the reaction yield, simplify the purification process, the resulting product purity of up to 99.8%.
BMS researchers successfully realized the single-kilogram synthesis of BMS-986260 using the process, providing a strong guarantee for the follow-up clinical research and clinical application of the drug.
References: 1. Development of a Scalable Synthesis of The Small TGF beta R1 PlayAtS-986260, 2020; 2. Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGF beta R1 as an an-Beta-Oncology Agent, 2020.