* 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.
With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 70℃; for 0.5 h;
S2. 1.9 g of 3-amino-5-methylpyrazole (2),15mL concentrated hydrobromic acid,2.8g cuprous bromide mixed into 100mL three-necked flask,Heated to 70 ;Take about 1.5g sodium nitrite dissolved in 5mL water,Using a constant pressure funnel slowly dropping into a three-necked flask;After the addition is completed,The reaction solution was stirred at 70 for 30min,After cooling to room temperature, 20 mL THF was added,20mL water;The mixture was extracted three times with 30 mL of ether, the organic layer was washed with sodium thiosulfate solution, dried over magnesium sulfate, filtered through silica gel,The solvent was distilled off under reduced pressure to give 3-methyl-5-bromopyrazole (3) in a yield of 62percent;
52%
at 70℃; for 0.5 h;
1.9 g of 3-amino-5-methylpyrazole (19), 15 mL of concentrated hydrobromic acid, and 2.8 g of cuprous bromide were placed in a 100 mL three-necked flask and heated to 70 °C.Approximately 1.5 g of sodium nitrite was dissolved in 5 mL of water and slowly added dropwise to a three-necked flask using a constant pressure funnel.After the completion of the addition, the reaction solution was stirred at 70 ° C for 30 min, then cooled to room temperature, and 20 mL of THF (tetrahydrofuran) and 20 mL of water were added.It was extracted three times with 30 mL of diethyl ether. The organic layer was washed with sodium thiosulfate solution and dried over magnesium sulfate.After filtration with silica gel, the solvent was evaporated under reduced pressure to give 1.7 g of 3-methyl-5-bromopyrazole (20) in a yield of 52percent.
Reference：
[1] Patent: CN104844567, 2017, B, . Location in patent: Paragraph 0031; 0035; 0040; 0045
[2] Patent: CN108191822, 2018, A, . Location in patent: Paragraph 0059; 0060; 0061
2
[ 31230-17-8 ]
[ 1229236-86-5 ]
Yield
Reaction Conditions
Operation in experiment
22%
Stage #1: With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 1 h; Stage #2: With hydrogenchloride In 2-methyltetrahydrofuran; water Stage #3: With sodium hydroxide In butan-1-ol
Prepare active catalyst by combining palladium chloride (160 mg, 0.90 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.10 g, 1.84 mmol) in DMF (25 mL) and warming to form a solution. Add the preformed catalyst to a solution of 3-methyl-1H-pyrazol-5-amine (3.0 g, 29.65 mmol), 4-((6-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholine hydrochloride (9.0 g, 20.19 mmol), potassium bicarbonate (6.0 g, 59.93 mmol) in DMF (65 mL) and heat to 150° C. for 1 h. Cool the reaction to 60° C. and add mercaptopropyl functionalized silica (500 mg) and stir for 1 h then filter to remove the silica. Cool to ambient temperature, add 2-methyltetrahydrofuran (125 mL) and extract with water to remove DMF. Add HCl to the organic solution to form the 3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine hydrochloride salt. Add the HCl salt (1.1 g) to sodium hydroxide (10 mL, 1N) in n-butanol (10 mL) and stir. Filter the resulting mixture to obtain 0.22 g of the free base, imidazo[1,2-b]pyridazin-6-amine, 3-[(4-chloro-2-fluorophenyl)methyl]-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(4-morpholinylmethyl), (22percent yield, M+1.=470).
2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.3%
With triethylamine; diisopropylamine; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 0.5h;
0.97 g of 3-amino-5-methylpyrazole and the acid binding agent were dissolved in tetrahydrofuran in 100 ml of a three-necked flask, and 2-formyl-3-oxo Ethyl propionate was added, and the mixture was stirred at 0 ° C for 0.5 h.After the reaction was completed, the temperature was raised to room temperature. After evaporation of the solvent, 100 ml of distilled water was added and the aqueous phase was extracted with ethyl acetate (100 x 3 ml). The organic phase was dried over anhydrous sodium sulfate for 20 minutes and concentrated to 1.95 g of intermediate I, The crude product was purified by silica gel column chromatography (eluent was a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 2) to give 1.77 g of intermediate I extract in a yield of 86.3percent; wherein the 2-formyl -3-oxo-propionic acid ethyl ester, 3-amino-5-methylpyrazole, acid binding agent, tetrahydrofuran in a weight ratio of 1: 1: 1.2: 4; a fluoric acid agent is triethylamine, diisopropylamine, Diisopropylethylamine, and the weight ratio is 3: 4: 1;
2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
In ethanol; at 20 - 80℃; for 2h;Inert atmosphere;
3-Methyl-1H-pyrazol-5-amine (3.8 g, 35.0 mmol) was added at rt to a stirred solution of ethyl 2- formyl-3-oxopropanoate (5.0 g, 34.7 mmol) in EtOH (50.0 mL). The resulting reaction mixture was stirred at 80 °C under nitrogen for 2 h. The formed solid was filtered off and dried under vacuum which gave the title compound (4.0 g, 56percent) as a solid. LCMS (ES+) M/z 206.25 [M+H]+.
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