[CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].CC([O-])(C)C.[K+].CS(C)=O.[Li+].[OH-:18].C1(S([C:28]2C(C(C3C=CC=CC=3Cl)=O)=CC=[CH:30][N:29]=2)(=O)=O)C=CC=CC=1.C(O)(=O)C.[Na+].[Cl-].C(O)(=O)C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1.Cl[C:68]1C=CC=CC=1C(C1C(C=C(O)C2C=CN=CC=2)=NC=CC=1)=O>CS(C)=O.C(OC(C)C)(=O)C.C(O)(=O)C1C=CC=CC=1.ClC1C=CC=CC=1C(C1C(C=C(O)C2C=CN=CC=2)=NC=CC=1)=O.C1(C)C=CC=CC=1>[C:1]([C:2]1[CH:4]=[CH:30][N:29]=[CH:28][CH:3]=1)(=[O:18])[CH3:68]
Charge powdered KOtBu (221.1 g, 1.93 moles, 1.40 eq.) to Reactor A, then charge DMSO (2 L) at 25° C. over 10 min. The KOtBu/DMSO solution is stirred for 30 min at 23° C., then a solution of 4-acetyl pyridine (92 mL, 2.07 moles, 1.50 eq) in DMSO (250 mL) is prepared in reactor B. The contents of reactor B are added to Reactor A over 10 minutes, then the Reactor A enolate solution is stirred at 23° C. for 1 h. In a separate 12-L flask (Reactor C), solid LiOH (84.26 g, 3.45 moles, 2.0 eq) is poured into a mixture of (2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone (500.0 g, 1.34 moles, 1.0 eq) and DMSO (2 L), with stirring, at 23° C. The enolate solution in reactor A is then added to Reactor C over a period of at least 15 minutes, and the red suspension warmed to 40° C. The reaction is stirred for 3 h, after which time HPLC analysis reveals less than 2% (2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone. Toluene (2.5 L) is charged, and the reactor temperature cooled to 30° C. The mixture is quenched by addition of glacial acetic acid (316 mL, 5.52 moles, 4.0 eq), followed by 10% NaCl (2.5 L). The biphasic mixture is transferred to a 22-L bottom-outlet Morton flask, and the aqueous layer is removed. The aqueous layer is then extracted with toluene (750 mL). The combined organic layers are washed with 10% NaCl (750 mL), then concentrated to 4 volumes and transferred to a 12-L Morton flask and rinsed with isopropyl acetate (4 vol, 2 L). The opaque amber solution is warmed to 75 degrees to 75° C. over 40 min. Benzoic acid (171.1 g, 1.34 moles, 1.0 eq) is dissolved in hot isopropyl acetate (1.5 L), and charged to the crude free base solution over at least 30 min. The crude solution containing benzoate salt is stirred for 0.5 h at 75° C. then cooled to 23° C. When solids are first observed, the cooling is stopped and the mixture is aged for an hour at the temperature at which crystals are first observed. Alternatively, if seed crystal is available, the mixture may be seeded with (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate (2.25 g) at 75° C., followed by stirring for 0.5 h at 75° C., then cooling to 23° C. over at least 1.5 h. The mixture is then cooled to <5° C., then filtered through paper on a 24 cm single-plate filter. The filter cake is then rinsed with cold i-PrOAc (750 mL) to produce granular crystals of bright orange-red color. The wet solid is dried at 55° C. to produce 527.3 g (83% yield) with 99.9% purity. (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate. Anal. Calcd. for C26H19N2ClO4: C, 68.05; H, 4.17; N, 7.13. Found: C, 67.89; H, 4.15; N 6.05. HRMS: calcd for C19H13ClN2O2, 336.0666. found 336.0673.
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