AiZynth impact on medicinal chemistry practice at AstraZeneca

Abstract

AstraZeneca chemists have been using the AI retrosynthesis tool AiZynth for three years. In this article, we present seven examples of how medicinal chemists using AiZynth positively impacted their drug discovery programmes. These programmes run the gamut from early-stage hit confirmation to late-stage route optimisation efforts. We also discuss the different use cases for which AI retrosynthesis tools are best suited.

Fig. 1. A) AiZynthFinder-proposed synthesis of 1. B) Laboratory synthesis of 1: i) Ni(ii)Cl₂·6H₂O (1 equiv.), NaBH₄ (4 equiv.), MeOH, 0 °C, 1 h, 96% yield; ii) isobutyl chloroformate (1 equiv.), N-methylmorpholine (1 equiv.), 5 (1 equiv.), 0 °C; then AcOH, 70 °C, 16 h, 93% yield; iii) HCl, MeOH, rt, 1 h, 92% yield.

Fig. 2. Example of AiZynth proposing a commercial starting material to a desired intermediate. Additional substitution has been omitted to focus on desired reactivity.

Fig. 3. Example of AiZynth's impact on DOS: an unorthodox Sonogashira reaction carried out on boronate 13 without deleterious Suzuki reactivity yielded high value synthetic intermediate 14.

Fig. 4. A) AiZynthfinder-proposed synthesis of 15. B) Laboratory synthesis of 15: i) Na₂CO₃ (2 equiv.), water, 100 °C, 16 h, 32% yield, 3 : 1 r.r.; ii) AcOH, 80 °C, 90 min; then HCl, 100 °C, 1 h, 13% yield.

Fig. 5. A) Two one-step retrosyntheses strung together to form a proposal for the synthesis of 20. The numbers in the diamond nodes represent the rank of the prediction, by feasibility. B) Laboratory synthesis of 20: i) n-BuLi (1.25 equiv.), Et₂O, −78 °C to rt, 2 h, 64% yield; ii) imidazole (1.5 equiv.), TBSCl (1.2 equiv.), DCM, 0 °C to rt, 80% yield; iii) NH₄OAc (10 equiv.), Na[(BH₃)CN] (2 equiv.), MeCN/MeOH, 65 °C, 1 h, carried crude; iv) Boc₂O (1.5 equiv.), NEt₃ (3 equiv.), DCM, rt, 1 h, 30% yield; v) CuCl₂ (0.2 equiv.), acetone/water, 80 °C, 2 h, 70% yield.

Fig. 6. A) Two one-step retrosyntheses strung together for an AI-proposed synthesis of 27. Blue borders indicate commercial availability. B) Laboratory synthesis of 27: i) EDC (1.5 equiv.), HOBt (1.5 equiv.), NaHCO₃ (3 equiv.), DMF, 60 °C, 3 h; ii) 3:1 DCM/TFA, rt, 2 h, 93% yield; iii) 8-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1 equiv.), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (1 equiv.), 1-methylimidazole (1 equiv.), DMF, rt, 16 h, 34% yield.

Fig. 7. A) Two retrosynthetic strategies for appending pyrazole solvent tail. Left: S_NAr strategy. Right: Cross-coupling strategy. B) Three proposals from AiZynth for synthesizing 37. C) Laboratory synthesis of 40via decarboxylative iodination: i) NIS (2 equiv.), LiOAc (0.2 equiv.), AcOH/water, 50 °C, 24 h, 92% yield; ii) 36 (1 equiv.), 38 (2 equiv.), CuI (0.30 equiv.), rac-trans-N¹,N²-dimethylcyclohexane-1,2-diamine (0.20 equiv.), Cs₂CO₃ (1.5 equiv.), dioxane, 120 °C, 24 h, product detected.