77% |
|
3-Amino-4-bromopyrazole (5 g, 30.9 mmol) and 4-methoxybenzyl chloride (21 g, 134 mmol, 4.3 equiv.) werecombined in anhydrous DMF (25 mL) and added dropwise to a stirred suspension of sodium hydride (60% dispersionin mineral oil, 6.25 g, 156 mmol, 5 equiv.) in anhydrous DMF (50 mL). The presuming suspension was stirred 2 days atroom temperature. Water (300 mL) was added slowly and the resulting mixture was extracted with ether (4 x 350 mL).The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 10% to 20% ethyl acetate-hexanes. The product, a white solid, is obtained as a 60:40 mixture of the 1-benzylated-1 H product and the 2-benzylated-2H product (14.96 g total, 93% yield). The compound from Preparative Example 100-C (10 g, 19.15 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.95 g, 57.42 mmol, 3.0 equiv.) were combined in 120 mL dimethoxyethane. 2M sodiumcarbonate solution (30 mL, 60 mmol, 3.1 equiv.) was added followed by tetrakis(triphenylphosphine) palladium(0) (2.36g, 2.04 mmol, 0.11 equiv.). The mixture was stirred 16 hours at 90 C. After cooling to room temperature, water (200mL) and brine (50 mL) were added and the mixture was extracted with ethyl acetate (2 x 200 mL). The extracts werecombined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 33%to 66% ethyl acetate-hexanes. The 1-benzylated-1 H product (Rf = 0.27 in 66% ethyl acetate-hexanes) elutes first,followed by the 2-benzylated-2H-product (Rf= 0.19 in 66% ethyl acetate-hexanes). The product is obtained as a yellowsolid (5.60 g total, 56% yield) with an isomeric ratio of 62:38. The compound from Preparative Example 110-C (4.3 g, 8.22 mmol) was dissolved in trifluoroacetic acid (70mL) and stirred 17 hours at reflux. After cooling, the trifluoroacetic acid was removed under reduced pressure. Theresulting residue was dissolved in tetrahydrofuran (100 mL), methanol (50 mL) and 4N aqueous sodium hydroxidesolution (25 mL, 100 mmol, 12 equiv.). The mixture was stirred 4 hours at 70 C then cooled to room temperature. Themixture was concentrated and the residue was suspended in brine (100 mL) and water (40 mL). This mixture wasextracted with 20% isopropanol in ethyl acetate (8 x 100 mL). The extracts were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in 10% methanol in dichloromethaneand purified by silica gel, chromatography using 10% methanol-dichloromethane followed by 10% 7N ammoniain methanol-dichloromethane. The product is obtained as a tan to brown solid (1.03 g, 77% yield). |