{"id":4932,"date":"2025-08-22T15:42:52","date_gmt":"2025-08-22T15:42:52","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/?post_type=case-study&p=4932"},"modified":"2026-02-05T17:07:12","modified_gmt":"2026-02-05T17:07:12","slug":"rp-6306-lunresertib","status":"publish","type":"case-study","link":"https:\/\/www.sygnaturediscovery.com\/fr\/case-study\/rp-6306-lunresertib\/","title":{"rendered":"RP-6306, Lunresertib\u00ae"},"content":{"rendered":"\n

Chemical development and process optimization for the synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H<\/em>-pyrrolo[2,3-b<\/em>]pyridine-3-carboxamide, an orally bioavailable and selective PKMYT1 inhibitor.<\/h3>\n\n\n
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\n Original MedChem Synthesis\n <\/div>\n <\/th>\n
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\n Optimized Process\n <\/div>\n <\/th>\n <\/tr>\n <\/thead>\n \n
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Lengthy 9 steps synthesis<\/p>\n\n <\/div>\n <\/div>\n <\/td>\n \n \n \n \n \n

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5 steps (including a one-pot hydration\/demethylation sequence)<\/p>\n\n <\/div>\n <\/div>\n <\/td>\n <\/tr>\n

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12% overall yield (79% avg. yield per step) to racemic product<\/p>\n\n <\/div>\n <\/div>\n <\/td>\n \n \n \n \n \n

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37% overall yield (82% avg. yield per step)<\/p>\n\n <\/div>\n <\/div>\n <\/td>\n <\/tr>\n

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7 chromatographic purifications<\/p>\n\n <\/div>\n <\/div>\n <\/td>\n \n \n \n \n \n

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Column chromatography-free process<\/p>\n\n <\/div>\n <\/div>\n <\/td>\n <\/tr>\n

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GMP synthesis successfully reproduced on kg scale (third party, Org. Process Res. Dev. 2025, ASAP)<\/p>\n\n <\/div>\n <\/div>\n <\/td>\n <\/tr>\n <\/tbody>\n\n <\/table>\n <\/div>\n<\/div>\n\n<\/div>\n\t\t\n\t <\/section>\n\n\n\n

<\/div>\n\n\n\n
\"Reagents
Reagents & conditions<\/strong>: (a) NaNO2<\/sub>, H2<\/sub>SO4<\/sub>, water, 88%; (b) POBr3<\/sub>, DMF, Toluene, 91%; (c) 1, Pd2<\/sub>(dba)3<\/sub>, Xantphos, Cs2<\/sub>CO3<\/sub>, (80%); (d) Malononitrile, NaOt<\/sup><\/em>Bu, Pd(dppf)Cl2<\/sub>.<\/sup>CH2<\/sub>Cl2<\/sub>, DME, (78%); (e) H2<\/sub>SO4<\/sub>, MeSO3<\/sub>H, H2<\/sub>O, then (f) DL-methionine, (75%).<\/figcaption><\/figure>\n\n\n\n
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Sygnature Discovery undertook the chemical development and process optimization for RP-6306, Lunresertib\u00ae (WO 2020\/195781 A1 & J. Med. Chem. 2022, 65, 15, 10251-10284), an orally bioavailable and selective inhibitor of PKMYT1, a promising therapeutic target implicated in various cancer pathologies. Given its potential in oncology, efficient access to this complex pyrrolopyridine-based molecule was critical for advancing preclinical and clinical investigations.<\/p>\n\n\n\n

The original medicinal chemistry synthesis was cumbersome, consisting of nine linear steps yielding a modest 12% overall yield (79% average yield per step). It also required seven chromatographic purifications, posing significant challenges for scalability, economic viability, and transferability into GMP environments.<\/p>\n\n\n\n

Leveraging our expertise in chemical process optimization, Sygnature Discovery streamlined the route significantly, reducing the process to five efficient steps, notably incorporating a strategically advantageous one-pot hydration\/demethylation sequence. The optimized synthetic approach delivered a dramatically enhanced overall yield of 37% (82% average yield per step) and entirely eliminated the need for column chromatography, thus significantly simplifying scale-up and GMP manufacturing.<\/p>\n\n\n\n

The robustness and practicality of our optimized route were confirmed by a successful third-party GMP reproduction at kilogram scale, now published in Organic Process Research & Development (2025, ASAP). Additionally, while both original and optimized routes culminated in a chiral SFC purification, our integrated analytical-to-kilogram scale SFC capabilities ensured seamless progression without presenting a bottleneck.<\/p>\n\n\n\n

This significant improvement not only highlights our strength in chemical process innovation but also underscores our ability to meet critical scalability and technology transfer requirements, essential for transitioning RP-6306 efficiently into advanced preclinical and subsequent clinical development phases.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

WO 2020\/195781 A1 & J. Med. Chem.
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