Retrosynthesis for
complex targets

Charge 3,5‑dichloropyrazine‑2‑carboxamide (1.0 eq, limiting) and 1‑methyl‑3‑[(3R)‑piperidin‑3‑yl]imidazolidin‑2‑one (1.05–1.2 eq, free base or its HCl salt) into anhydrous DMSO (or NMP/MeCN), add DIPEA (2.5–3.0 eq) and stir the mixture under nitrogen at 60–80 °C for 4–16 h, monitoring by LC‑MS for consumption of the dichloride (mono‑SNAr occurs selectively at C‑5, the position remote from the carboxamide, leaving the C‑3 chloride intact for the subsequent Buchwald/SNAr aniline coupling). Cool to room temperature, drown into water/brine, collect the precipitated solid by filtration or extract with EtOAc/DCM‑iPrOH, dry (Na2SO4) and concentrate. Purify by silica chromatography (0–10% MeOH/DCM) or reverse‑phase prep‑HPLC/trituration to give the 5‑amino‑3‑chloropyrazine‑2‑carboxamide as an off‑white solid.

To a solution of 4-(4-nitrophenyl)piperidine (1.0 eq, often used as the free base or liberated in situ from its HCl salt with Et3N/DIPEA) and tert-butyl 4-formylpiperidine-1-carboxylate (1.1–1.3 eq) in 1,2-dichloroethane (or DCM/THF) under nitrogen is added glacial acetic acid (0.1–1.0 eq), and the mixture is stirred at room temperature for 30–60 min to allow iminium/hemiaminal formation. Sodium triacetoxyborohydride (1.5–2.0 eq) is then added portionwise at 0 °C–rt and the mixture is stirred at room temperature for 12–18 h. The reaction is quenched with saturated aqueous NaHCO3, extracted with DCM (or EtOAc), the combined organics washed with brine, dried over Na2SO4, concentrated, and the crude bis-piperidine purified by silica chromatography (0–10% MeOH/DCM with 1% NH4OH, or EtOAc/heptane) to give the Boc-protected product, typically in 70–90% yield.

Dissolve the nitroarene (1.0 eq) in MeOH/EtOAc (or THF/MeOH ~1:1) to give a ca. 0.1 M solution, add 10% Pd/C (10–20 wt %, 50% water-wet) under a nitrogen blanket, then purge the vessel and stir vigorously under a hydrogen atmosphere (balloon or 1–4 bar Parr) at room temperature for 3–16 h until TLC/LCMS shows full conversion of the nitro compound to the aniline. Filter the mixture through a pad of Celite, rinsing with MeOH/DCM, and concentrate under reduced pressure; the crude aniline is usually of sufficient purity to carry forward, or can be purified by silica chromatography (0–10% MeOH/DCM with 1% NH4OH). If catalytic hydrogenation is problematic on scale, an equivalent result is obtained with Fe powder (5 eq)/NH4Cl (5 eq) in EtOH–H2O (4:1) at 70–80 °C for 1–2 h.

Combine 3-chloro-5-[(3R)-3-(4-methyl-3-oxopiperazin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide (1.0 eq), the tert-butyl 4-{[4-(4-aminophenyl)piperidin-1-yl]methyl}piperidine-1-carboxylate aniline (1.1–1.2 eq), Cs2CO3 (2.0–2.5 eq), Pd2(dba)3 (5 mol %) and Xantphos (10 mol %) in degassed 1,4-dioxane in a sealed vial, then sparge with N2 for 5–10 min. Heat the mixture at 95–105 °C (oil bath or microwave at 120 °C for 1–2 h) for 12–16 h, monitoring by LC-MS for consumption of the chloropyrazine. Cool, dilute with EtOAc/water (or filter through Celite), extract, dry over Na2SO4, concentrate, and purify by silica chromatography (0–10% MeOH/DCM) or reverse-phase prep-HPLC to give the Boc-protected coupled aniline. (An acid-promoted SNAr — the aniline, 1.05 eq, with cat. p-TsOH·H2O or 4 M HCl/dioxane in NMP/iPrOH at 100–120 °C — is a viable Pd-free alternative given the carboxamide-activated 3-chloropyrazine.)

The Boc-protected bis-piperidine intermediate was dissolved in dichloromethane (or 1,4-dioxane) and treated with 4 M HCl in 1,4-dioxane (10–20 equiv) at 0 °C, then stirred at room temperature for 1–4 h until LC-MS showed complete consumption of the carbamate. The volatiles were removed under reduced pressure and the residue was triturated with diethyl ether (or MTBE) and dried under vacuum to give the secondary amine as the hydrochloride salt, which was used directly in the subsequent reductive amination/SNAr step without further purification. If the free base was required, the residue was partitioned between DCM/MeOH (9:1) and saturated aqueous NaHCO3 (or passed through an SCX-2 cartridge eluting with 2 M NH3/MeOH).

5-Bromopyridine-2-carboxylic acid (1.0 eq) is dissolved in anhydrous DMF (~0.15 M) and treated with HATU (1.1–1.3 eq) and DIPEA (3.0–4.0 eq) at 0 °C, and the mixture is stirred 10–20 min to pre-activate the acid. 3-Aminopiperidine-2,6-dione hydrochloride (1.05–1.2 eq) is then added in one portion and the reaction is allowed to warm to room temperature and stirred 4–16 h under nitrogen, with monitoring by LC–MS. The mixture is diluted with water (or poured onto ice-water/brine), and the precipitated amide is collected by filtration, or the product is extracted into EtOAc/DCM, washed with saturated NaHCO₃, water and brine, dried over Na₂SO₄, concentrated and purified by silica chromatography (0–8% MeOH/DCM) or trituration from MeOH/Et₂O to give the coupled glutarimide amide. Reaction temperature is kept mild and base stoichiometry moderate to limit epimerisation of the acid-sensitive glutarimide stereocentre.

Combine the secondary piperidine (1.0 equiv, limiting) and 5‑bromo‑N‑(2,6‑dioxopiperidin‑3‑yl)pyridine‑2‑carboxamide (1.2–1.5 equiv) in anhydrous 1,4‑dioxane (or dioxane/t‑BuOH 4:1) in an oven‑dried vial, add Cs₂CO₃ (2.5–3.0 equiv), then sparge the mixture with N₂ for 5–10 min before adding RuPhos Pd G3 (0.10 equiv) and RuPhos (0.10 equiv). Seal and heat at 90–100 °C with stirring for 3–16 h (monitor by LC‑MS), then cool, dilute with DMSO/MeOH, filter through Celite and purify directly by reverse‑phase prep‑HPLC (0.1% formic acid or 10 mM NH₄HCO₃ modifier) to give the C–N coupled product, typically in 20–45% yield. Because the glutarimide C‑3 stereocentre epimerises under prolonged basic heating, keep the reaction time as short as conversion allows and neutralise/quench promptly; alternatively run the coupling with the free amine and install the glutarimide amide last if erosion of ee is observed.