4-AMINOBICYCLO[2.2.2]OCTANE-1-CARBOXYLIC ACID METHYL ESTER

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (500 mg, 2.73 mmol) (Yeh, V. S. C.; Kurukulasuriya, R.; Madar, D.; Patel, J. R.; Fung, S.; Monzon, K.; Chiou, W.; Wang, J.; Jacobson, P.; Sham, H. L.; Link, J. T. Bioorg. and Med. Chem. Let, 2006, vol. 16, #20 p. 5408-5413) in DCM (10 mL) at rt was added TEA (0.76 mL, 5.46 mmol) and DMAP (50 mg, 0.41 mmol). Cyclopropanesulfonyl chloride (764 mg, 5.46 mmol, Matrix) was added dropwise by syringe. The reaction mixture was stirred for about 15 h at rt. The mixture was washed with water (10 mL), and the aqueous layer was extracted with DCM (2×10 mL), the organic layers were combined and dried over anhydrous Na2SO4, filtered and concd in vacuo. The crude materials was purified by silica gel chromatography eluting with a gradient of 20-35% EtOAc in hexanes to afford methyl 4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (410 mg, 52% yield). LC/MS (Table 1, Method p) Rt=1.68 min; MS m/z: 288 (M+H)+. The mixture was washed with water (10 mL) the aqueous layer was extracted with DCM (2×10 mL) dried over anhydrous Na2SO4 filtered The crude materials was purified by silica gel chromatography eluting with a gradient of 20-35% EtOAc in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 4-(4-(trifluoromethyl)phenylsulfonamido)bicyclo[2.2.2]octane-1-carboxylate was prepared from 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester and 4-trifluoromethylbenzene sulfonamide using a method analogous to the method used to prepare Intermediate 1.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 80 mg 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (75% purity, 0.181 mmol) from Example 4A, 76 mg of HATU (0.199 mmol) and 94 μl (0.542 mmol) of N,N-diisopropylethylamine in 0.54 ml of DMF was stirred at RT for 10 min Subsequently, 40 mg (0.217 mmol) of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate were added and the mixture was stirred at RT overnight. The reaction mixture was admixed with water and acetonitrile and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid). 62 mg of the target compound were obtained (70% of theory). the mixture was stirred at RT overnight purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid)