* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Method B, in the 28 °C constant temperature in the water bath, to 50 ml of the three flasks, input 6.28 g (0.025 μM) 2, 4 - dichloro - 1, 1, 1 - trifluoro -2 - ene butyl butyl ether, 15.0 g acetic acid (14.3 ml) and 5.4 g water (5.4 ml), stirring slowly dripping 8.35 g 40percent aqueous solution of methyl hydrazine (wherein methyl jingjing mole number is 0.073 μM), dropping time is 5 minutes, and then remain at room temperature 1 hour. To recover the acetic acid by distillation, the remaining product after the water washing, drying, to obtain 3.35 g 1 - methyl -3 - (trifluoromethyl) - 1 - H - pyrazole, and the yield is 89percent.
Reference：
[1] Patent: CN106916107, 2017, A, . Location in patent: Paragraph 0055; 0056; 0058
2
[ 60-34-4 ]
[ 154471-65-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
With acetic acid In water at 20 - 28℃; for 1 h;
Method A, in the 28 °C constant temperature in the water bath, to 50 ml of the three flasks, input 7.2 g (0.025 μM) 2, 2, 4 - trichloro - 1, 1, 1 - trifluoro-butyl butyl ether, 15.0 g acetic acid (14.3 ml) and 5.4 g (5.4 ml) water, in the stirring slowly dripping 8.35 g 40percent aqueous solution of methyl hydrazine (wherein methyl jingjing mole number is 0.073 μM), dropping time is 5 minutes, and then remain at room temperature 1 hour. To recover the acetic acid by distillation, the remaining product after the water washing, drying, to obtain 3.2 g 1 - methyl -3 - (trifluoromethyl) - 1 - H - pyrazole, and the yield is 85percent.
Reference：
[1] Patent: CN106916107, 2017, A, . Location in patent: Paragraph 0055; 0056; 0057
Reference：
[1] European Journal of Organic Chemistry, 2002, # 17, p. 2913 - 2920
[2] Patent: WO2007/43677, 2007, A1, . Location in patent: Page/Page column 485-486
[3] Patent: US2011/160188, 2011, A1, . Location in patent: Page/Page column 4; 11
5
[ 59938-06-6 ]
[ 60-34-4 ]
[ 153085-15-5 ]
[ 154471-65-5 ]
Yield
Reaction Conditions
Operation in experiment
24 g
at 55℃; for 20 h; Cooling with ice
ETFBO (270 g, 1.61 mol, 1.00 eq) was dissolved in methanol (750 mL). The solution was cooled in an ice/water-bath and methyl hydrazine (88.3 mL, 77.7 g, 1.69 mol, 1.05 eq) was added dropwise within 20 minutes. The mixture was heated to 55°C and stirred at this temperature for 20 h in dry air (drying tube). Successively the solvent was removed and the residue distilled under vacuum : 1st Fraction : 150 mbar, 130°C bath temperature, 73~85°C, mixture of isomers, 129 g.2nd Fraction : 70 mbar, 150°C bath temperature, 75~85°C, 1-methyl-3-(trifluoromethyl)-1H-pyrazole, 24 g. Overall yield : 153 g (1.02 mol) 63 percent.
The solution was cooled in an ice/water-bath and methyl hydrazine (88.3 mL, 77.7 g, 1.69 mol, 1.05 eq) was added dropwise within 20 minutes. The mixture was heated to 55°C and stirred at this temperature for 20 h in dry air (drying tube). Successively the solvent was removed and the residue distilled under vacuum : 1st Fraction : 150 mbar, 130°C bath temperature, 73~85°C, mixture of isomers, 129 g. 2nd Fraction : 70 mbar, 150°C bath temperature, 75-85 °C, l-methyl-3-(trifluoro- methyl)-lH-pyrazole, 24 g. Overall yield : 153 g (1.02 mol) 63 percent.
2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid: <strong>[154471-65-5]1-methyl-3-trifluoromethyl-1H-pyrazole</strong> (1.00 g, 6.66 mmol) was dissolved in THF (25 mL) in an oven-dried round bottom flask and cooled to-78 C in an acetone/dry ice bath. 2.5 M n-butyl lithium/hexane (3.196 ml, 7.99 mmol) was added drop wise to the stirred solution followed by drop wise addition of triisopropyl borate (5.01 g, 26.64 mmol). The mixture was warmed to room temperature and stirred for three hours. The reaction mixture was adjusted to pH 6 with IN HCl solution followed by the removal of THF under vacuum. The aqueous phase was extracted with EtOAc (3x100 ml). The combined organic phase was washed with brine and dried over anhydrous MgS0(sub>4, filtered and evaporated to give 2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid (1.12 g, 5.80 mmol, 87 % yield) as a white solid: LCMS m/z (%) = 195 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) delta: 8.37-8.40 (m, 2H), 7.57 (dd, J= 4.0 Hz, 1H), 4.06 (s, 3H).
Preparation 7[1 -Methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yllboronic acidTo a stirred solution of 1 -methyl-3-(thfluoronnethyl)-1 H-pyrazole (1 .89 g, 12.6 mmol) in anhydrous tetrahydrofuran (20 ml_) under nitrogen cooled to -78C was added n- butyllithium (8.3 mL, 1 .6 M solution in hexanes, 13.2 mmol) slowly over 5 minutes. The resulting yellow solution was stirred at -78C for 1 hour and trimethyl borate (1 .56 mL, 13.9 mmol) was then added slowly. The reaction flask was covered in foil and allowed to warm to room temperature for 16 hours. The white solution was quenched with aqueous 1 M hydrogen chloride solution (10 mL) and stirred at room temperature for 1 .5 hours. The mixture was extracted with ethyl acetate (2 x 30 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo to give an off-white foam (2.1 1 g). The foam was triturated with dichloromethane, filtered and dried in vacuo to afford the title compound as a white solid (1 .57 g, 64%).1H NMR (400 MHz, MeOH-d4): delta 4.04 (s, 3H), 6.89 (s, 1 H).LCMS Rt = 1 .1 1 minutes MS m/z 194 [MH]+ 192 [M-H]-,
With hydrogenchloride; diisopropylamine; In tetrahydrofuran;
4B Preparation of <strong>[154471-65-5]1-methyl-3-trifluoromethylpyrazol</strong>-5-yl-boronic acid A solution of <strong>[154471-65-5]1-methyl-3-trifluoromethylpyrazol</strong> (2 g) in 10 ml THF is cooled under an inert gas atmosphere to -78 C. A 2 M solution of LDA (9.75 ml) is added dropwise. The mixture is stirred to 10 C. for 1 h and cooled to -75 C. Trimethylborate (5.8 ml) is added and after stirring for 1 h at -75 C. the mixture is stirred overnight at ambient temperature. The resulting reaction solution is added to 10% hydrochloric acid (15 ml). The water phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with water and a saturated sodium chloride solution. The organic phase is dried and evaporated and the residue is crystallized from water. After drying, one obtains the title compound as nearly colorless crystals (1.12 g) of mp. 138 C.
With hydrogenchloride; diisopropylamine; In tetrahydrofuran;
4B Preparation of <strong>[154471-65-5]1-methyl-3-trifluoromethylpyrazol</strong>-5-yl-boronic acid A solution of <strong>[154471-65-5]l-methyl-3-trifluoromethylpyrazol</strong> (2 g) in 10 ml THF is cooled under an inert gas atmosphere to -78 C. A 2 M solution of LDA (9.75 ml) is added dropwise. The mixture is stirred to 10 C for 1 h and cooled to -75 C. Trimethylborate (5.8 ml) is added and after stirring for 1 h at -75 C the mixture is stirred overnight at ambient temperature. The resulting reaction solution is added to 10 % hydrochloric acid (15 ml). The water phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with water and a saturated sodium chloride solution. The organic phase is dried and evaporated and the residue is crystallized from water. After drying, one obtains the title compound as nearly colorless crystals (1.12 g) of mp. 138C.
To a mixture of 8.71 g of l-methyl-3-trifIuoromethyl-1H-' pyrazole and 130 ml of tetrahydrofuran was added dropwise 32 ml of a 2.0 mol/L lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at -78C. The mixture of stirred at -780C for 2 hours and then poured into a mixture was dry ice and 50 ml of tetrahydrofuran. The mixture was stirred for 2 hours while allowing it to rise to around room temperature. Water and diethyl ether were poured into the reaction mixture. The aqueous layer was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then layers were separated. The resulting aqueous layer was washed with diethyl ether two times, adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 8.19 g of l-methyl-3- tri f luoromethyl- lH-pyra zole- 5-carboxylic acid of the formula :l-Methyl-3-trifluoromethyl-lH-pyrazole-S-carboxylic acid EPO <DP n="488"/>1H-NMR (CDCl3, TMS) delta (ppm) : 4.13 (3H, s) , 7.22 (IH, s).
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