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To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0°C, was slowly added NaH (60percent in mineral oil) (3.13 g, 78.133 mmol). The solution was stirred for 1 hour at 0°C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g , 71.03 mmol) was added slowly and the reaction was heated to 100°C overnight or until consumption of the pyrazole by NMR. The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCI (4 x 20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil. The oil was purified using silica gel chromatography eluting with 10percent EtOAc/hexanes to 25percent EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45percent yield) with a R^= 0.4 (25percent EtOAc/hexanes, using iodine as the stain). 1H NMR (CDCI3, 400 MHz) 8 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88(m, 2H), 1.47(s, 9H). |
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NaH (60percent in mineral oil, 1.36 g, 34 mmol) is added portionwise to a stirred solution of 4- bromopyrazole (4.58 g, 30.9 mmol) in DMF (20 ml). The resulting mixture is stirred for 1h at O0C and 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (as obtained in preparation 61 , 8.62 g, 30.9 mmol) is added. The resulting pale suspension is heated at 1000C for 1h. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion.(TM). (Isco Inc.) apparatus ( gradient hexanes: TBDME from 1 :0 => 0:1) to afford the title compound as a colorless solid, Rt = 1.213 min (Acquity UPLC BEH C18, 2.1x50mm, 1.7 micron, detection 215nM, 0.1 min 2percent CH3CN in H2O , 2percent to 100percent CH3CN in H2O in 1.5min, 0.4 min 100percent CH3CN + 0.1 percent TFA, flow rate 1.0ml/min); MS: 330 (M+1, 79Br)+. |
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As shown in step 3-ii of Scheme 3, to a solution of 4-bromopyrazole (4.68 g, 31.83 mmol) in DMF (300 mL) at 00C was added sodium hydride (60percent on mineral oil, 1.27 g, 31.83 mmol). The solution was stirred at 00C for one hour, at which point a solution of Compound 1013 (9.78 g, 31.83 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then refluxed for 16 hours. Disappearance of both starting materials was observed by TLC (1 : 1 EtOAc/hexanes). The reaction was cooled to room temperature, quenched by the addition of brine (300 mL), and extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with 1percent aqueous LiCl (3 x 200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude bromide was purified by silica gel chromatography (0 - 25percent EtOAc/hexanes) to give Compound 1014. |
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With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 80℃; for 12h; |
c) tert-Butyl 4-(4-bromo- 1 H-pyrazol- 1 -yl)piperidine- 1 -carboxylateTo a cooled solution of the compound of Intermediate Example 5(b) (6.7 g, 23.9 mmol) in DMF (50 ml) was added NaH (2.8 g, 1 19 mmol, 5 eq.) and 4-bromo-lH-pyra- zole (2.8 g, 19.1 mmol, 0.8 eq.) and stirred at 80 °C for 12 h. The mixture was quenched and extracted with ethyl acetate (3 chi 100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude product (8.0 g). |
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General procedure: To an ice-cooled solution of 4-bromo-1H-pyrazole (1.19 g, 8.07 mmol) in 10 mL of DMF was added portionwise sodium hydride (355 mg, 8.88 mmol, 60percent in oil). The resulting mixture was stirred for additional 1 h. Then to the mixture was added oxan-4-yl methanesulfonate (1.60 g, 8.88 mmol), which was prepared in a similar manner as described for 12. The resulting mixture was gradually heated to 100 °C and stirred for 10 h. After cooled to room temperature, the reaction was quenched with water. The mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1:6) to afford 26a as a white solid in 61percent yield. |
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With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 12h; |
To a cooled solution of the compound of Intermediate Example 5(b) (6.7 g, 23.9 mmol) in DMF (50 ml) was added NaH (2.8 g, 119 mmol, 5 eq.) and 4-bromo-1H-pyrazole (2.8 g, 19.1 mmol, 0.8 eq.) and stirred at 80° C. for 12 h. The mixture was quenched and extracted with ethyl acetate (3*100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude product (8.0 g). |
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With sodium hydride; In N,N-dimethyl-formamide; at 20 - 110℃;Inert atmosphere; |
Sodium hydride (400 mg, 60percent dispersion, 10 mmol) was added to a stirred solution of the bromopyrazole (1.47g, lOmmol) and 4-Methanesulfonyloxy-pipehdine-1-carboxylic acid tert-butyl ester (2.4 g, 8.6 mmol) in dry DMF (10 ml) at room temperature. After gas evolution had ceased, the reaction was stirred and heated at 110 0C under N2 for 4 h. The reaction mixture was allowed to cool to room temperature and stand at for 18 h before being partitioned between EtOAc and H2O. The organic layer was separated, washed with water H2O (x2), brine (x1 ), then dried (Na2SO4), filtered and the solvent removed in vacuo.The residue was purified using silica column chromatography running a 10-25percentEtOAc/petrol gradient to give a colourless oil (1.7 g, 5.15 mmol). 1 H NMR (400 MHz,CDCI3): 7.48 (1 H, s), 7.45 (1 H, s), 4.45-4.07 (3H, m), 2.90 (2H, t), 2.12 (2H, d), 1.97-1.79(2H, m), 1.50 (9H, s). |
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