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With triethylamine In tetrahydrofuran at 20℃; for 2 h;
4-Iodopyrazole (20 mmol) was treated with Et3N (30 mmol) and (Boc)2O (22 mmol) in THF (60 mL) at r.t. for 2 hours to form N-Boc-4-iodopyrazole (5.88 g, 100percent). N-Boc-4-iodopyrazolyle in THF (100 mL) was reacted with hexamethylditin (20 mmol) in the presence of Pd(Ph3P)4 (1.1 g, 1 mmol) under nitrogen at 78°C overnight. To it was added aqueous 10percent KF and the resulting mixture was stirred for 30 minutes, and then filtered through a pad of Celite. The filtrate was extracted with EtOAc. The EtOAc layer was washed with water, and dried over MgSO4. Filtration and concentration followed by purification of the mixture by column chromatography afforded the 3-trimethyltinpyrazole derivative (5 g, 75percent) as a white solid.
98%
With triethylamine In tetrahydrofuran at 20℃; for 3 h;
ieri-Butyl 4-iodo-1 H-pyrazole-1 -carboxylate (2); [00189] 4-lodopyrazole (1) (7.85g 40.4mmole) was dissolved in THF (120ml_) and triethylamine (8.5ml_, 6.12g 60.5mmole) and di-terf-butyl dicarbonate (9.7g, 44.5mmole) were added. The reaction was stirred at r.t. for 3 hours. The THF was evaporated and ethyl acetate (100ml_) was added. The solution was washed with water (2x50ml_) and with brine, then dried and evaporated to leave an oil (14.2g). The crude product was purified by chromatography on a pad of silica in a sinter (10cm diam, 6cm thick) eluted with 10percent ethyl acetate in cyclohexane (1 1 x90ml_), then 20percent ethyl acetate in cyclohexane (3x90ml_) to give the protected pyrazole 2 (1 1 .66g 98percent). 1H-NMR (CDCI3, 500MHz): δ 1 .68 (s, 9H), 7.73 (s, 1 H), 8.17 (s, 1 H).
98%
With triethylamine In tetrahydrofuran at 20℃; for 3 h;
tert-Butyl 4-iodo-1H-pyrazole-1-carboxylate (2) 4-Iodopyrazole (1) (7.85 g 40.4 mmole) was dissolved in THF (120 mL) and triethylamine (8.5 mL, 6.12 g 60.5 mmole) and di-tert-butyl dicarbonate (9.7 g, 44.5 mmole) were added. The reaction was stirred at r.t. for 3 hours. The THF was evaporated and ethyl acetate (100 mL) was added. The solution was washed with water (2*50 mL) and with brine, then dried and evaporated to leave an oil (14.2 g). The crude product was purified by chromatography on a pad of silica in a sinter (10 cm diam, 6 cm thick) eluted with 10percent ethyl acetate in cyclohexane (11*90 mL), then 20percent ethyl acetate in cyclohexane (3*90 mL) to give the protected pyrazole 2 (11.66 g 98percent). 1H-NMR (CDCl3, 500 MHz): δ 1.68 (s, 9H), 7.73 (s, 1H), 8.17 (s, 1H).
90%
at 20 - 35℃; Large scale
In the reaction kettle, add 4 - iodine pyrazole (1.94 kg, 10 μM) and tetrahydrofuran 5 kg, stirring to dissolve, heating to the 20 - 30 °C, slow carbon acid di-tert-butyl adds by drops two (2.18 kg, 10 μM), drop the temperature increases slightly, the control temperature of not more than 35 °C. The completion of the dropping, stirring 1 - 2 hours, TLC confirms the completion of the reaction. The reaction liquid under reduced pressure when the distillation is carried out to the does not flow the fluid, adding 1.2 kg normal heptane cooling to 0 °C beating, filtering, drying to obtain N - BOC - 4 - iodine pyrazole 2.65 kg, yield 90percent, HPLC: 97.4percent.
78.5%
With triethylamine In dichloromethane at 20℃;
General procedure: To a solution of pyrazole 1-5 (1 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (for 0.05mol of pyrazole – 50 mL of dichloromethane were user) Di-tert-butyl dicarbonate (1.2 equiv) wereadded at room temperature and left to stir overnight. Dichloromethane was washed with saturatedNaHCO3 solution (1×25 mL – for 50 mL of dichloromethane) then with deionized H2O (1 × 25mL). Organic layer was dried with anhydrous Na2SO4, and evaporated under reduced pressure.
Reference：
[1] Patent: EP946508, 2009, B1, . Location in patent: Page/Page column 58
[2] Patent: WO2012/123745, 2012, A1, . Location in patent: Page/Page column 64
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 32, p. 8290 - 8294[4] Angew. Chem., 2013, vol. 125, # 32, p. 8448 - 8452,5
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 10045 - 10065
[6] Patent: US2013/345181, 2013, A1, . Location in patent: Paragraph 0621; 0623
[7] Patent: CN106188116, 2016, A, . Location in patent: Paragraph 0018
[8] Arkivoc, 2014, vol. 2014, # 6, p. 54 - 71
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