Understanding Phase Behavior of Nearly Energetically Equivalent Polymorphs To Achieve Controlled Crystallization for a Nav1.7 Pain Inhibitor Compound

Abstract

GENE-A, a Nav1.7 inhibitor compound with analgesic activity, was developed as a crystalline anhydrate, for which two polymorphic forms, I and II, were discovered. The two forms were found to possess very similar free energies as determined experimentally with Form II being thermodynamically stable above 25 °C based on solubility measurements. A detailed solid-state characterization was conducted to determine the relative stability of these solid forms, and both thermodynamic and kinetic pathways (slurry bridging and crystallization) were evaluated. Form II was obtained as the final form in competitive slurries at RT. The outcome of crystallization experiments in terms of the solid form obtained was complicated and yielded variable results depending on the form of the starting material and that of the seeds. Form II was reproducibly obtained as the end product in unseeded experiments and in those with Form II as seeds and starting material, while Form I was obtained in all other seeded experiments. On the basis of the experimental data, a controlled crystallization strategy was developed, wherein Form II was used both as starting material and seeds to reproducibly obtain the desired form upon scale-up.

Improved Synthesis of the Nav1.7 Inhibitor GDC-0276 via a Highly Regioselective SNAr Reaction

“…11 Treatment with activated carbon (40 wt %) and recrystallization from 1-propanol was thus necessary to further upgrade the purity of the API to >99 A% HPLC. 12 In order to obtain the API with the desired polymorphic form I, 13 GDC-0276 seed crystals (1 wt %) were added to a supersaturated solution of GDC-0276 in 1-propanol at 70 °C, followed by slow cooling to 25 °C.…”

“…Unless otherwise noted all reactions were run under a nitrogen atmosphere, and solvents and reagents were used without further purification. 1 H NMR (300 MHz, 500 MHz, 600 MHz) and 13 First-Generation Synthesis. tert-Butyl-5-chloro-2,4-difluorobenzoate (1).…”

“…The crude product was dissolved in acetone (10.8 kg), and the mixture was treated with 0.2 wt % aqueous citric acid (106 kg, 1 mol, 2 mol %) at 0−5 °C for 1 h. The product was filtered and washed with water (2 × 25 kg). The cake was collected and dried under vacuum to afford 10.5 kg of 12 as a solid (69% yield, 99.5 A% HPLC): mp = 83 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.95 (br s, 1H), 3.94 (t, J = 7.7 Hz, 4H), 2.15 (p, J = 7.8 Hz, 2H), 1.45 (s, 9H); 13 Azetidine-1-sulfonamide (3). 34 A reactor was charged with dichloromethane (96.73 kg), 12 (7.30 kg, 30.9 mol, 100 mol %), and TFA (10.57 kg, 92.7 mol, 300 mol %), and the mixture was held at 25 °C for >14 h. HPLC analysis showed 12 to be <3 mg/mL.…”

“…The contents of the reactor were filtered through an Aurora filter and washed twice with CPME (5.18 kg each time). After no more filtrate could be collected from the filter, the cake was dried on the filter at 50 °C (jacket temperature) under vacuum with a nitrogen purge for ≥24 h. The process gave 2.72 kg of 3 (65% yield; 99.6 A% by GC) as an off-white solid: mp = 129 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.84 (s, 2H), 3.67 (t, 4H), 2.07 (p, 2H); 13 (9). A reactor was charged with water (19.44 kg), K 3 PO 4 (13.06 kg, 61.5 mol, 300 mol %), toluene (49.09 kg), 5 (8.10 kg, 20.5 mol uncorrected, 100 mol %), cyclopropylbor-onic acid (2.47 kg, 28.7 mol, 140 mol %), and XPhos (49 g, 103 mmol, 0.5 mol %).…”

“…Drying was continued for ≥24 h. The process gave 5.36 kg of 2 (88% yield; 99.8 A% HPLC purity) as an offwhite solid: mp = 298 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.79 (br s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 13.2 Hz, 1H), 3.64 (s, 2H), 2.03 (dt, 1H), 2.00 (t, 3H), 1.72 (m, 6H), 1.66 (s, 6H), 0.91 (m, 2H), 0.60 (m, 2H). 13 4-(Adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5cyclopropyl-2-fluorobenzamide, GDC-0276. A reactor was charged with toluene (31.90 kg), acid 2 (5.27 kg, 15.3 mol, 100 mol %), and 1,1-carbonyldiimidazole (3.10 kg, 19.1 mol, 125 mol %), and the mixture was heated to 50 °C and held at that temperature for >2 h. HPLC analysis showed 2 to be ≤2.0 A%.…”