Preparation background and overview of 6-hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile
6-Hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile is a pharmaceutical intermediate. There are reports in the literature that it can be used to prepare RET Inhibitors. 6-Hydroxy-4-(6-fluoro-3-pyridylmethoxypyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile can be prepared from (E)-4-bromo-6-methoxy Pyrazolo[1,5-a]pyridine-3-carboxaldehyde oxime is used as raw material and is prepared through a five-step reaction.
Preparation of 6-hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile
Preparation step 1 of 6-hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile: 3-cyano-4- Bromo-6-methoxypyrazolo[1,5-a]pyridine
Place (E)-4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxaldehyde oxime (10.0g, 37.026mmol) in a 500mL single-neck bottle with acetic anhydride (250mL ) was dissolved and placed under 140°C for reflux reaction. The solution gradually turned from yellow to brown. The reaction was completed after 4.5 hours of reaction by TLC. The solvent was distilled off under reduced pressure at this temperature, 100 mL of water was added to the residue, stirred for 5 minutes and then filtered with suction. The filter cake was washed with 20 mL of water, and the filter cake was dried in a vacuum drying oven at 50°C for 24 hours to obtain 6.83 g of gray solid with a yield of 73.2%. Rf=0.4(PE:EA=2:1).
Preparation step 2 of 6-hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile: 3-cyano-4- Bromo-6-hydroxypyrazolo[1,5-a]pyridine
Dissolve 3-cyano-4-bromo-6-methoxypyrazolo[1,5-a]pyridine (6.83g, 27.1mmol) in a 1000mL single-mouth bottle with DCE (273mL), once Add AlCl3 (10.8g, 81.0mmol), transfer to 80°C oil bath and reflux overnight. TLC detects that the reaction is complete. Cool the reaction solution to room temperature, add 200 mL of NaSO4·10H2O THF solution under stirring, stir for 4 hours and then filter with suction. Collect the filtrate and spin dry to obtain 5.8g of brown solid. . The yield is 90%. Rf=0.2(PE:EA=2:1).
Preparation step 3 of 6-hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile: 3-cyano-4- Bromo-6-ethoxypyrazolo[1,5-a]pyridine
Place 3-cyano-4-bromo-6-hydroxypyrazolo[1,5-a]pyridine (5g, 21.005mmol) and potassium carbonate (8.7g, 63mmol) in a 250mL single-neck bottle with DMA ( 125 mL) was dissolved, and ethyl iodide (5 g, 32.057 mmol) was added with stirring. After the addition was completed, the mixture was transferred to 60°C for reaction. After 6 hours of reaction, TLC detected that the reaction was complete. Add 40 mL of ammonia: water = 1:1 solution to the reaction solution, stir for 1 hour and then filter with suction. The filter cake is washed with 50 mL of water, spin-dried, and dried to obtain 4.48 g of gray solid, with a yield of 80.2%. Rf=0.95 (PE:EA=1:1).
Preparation step 4 of 6-hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile: 3-cyano-6- Ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine
Place 3-cyano-4-bromo-6-ethoxypyrazolo[1,5-a]pyridine (2.5g, 9.4mmol) and 2-fluoropyridine-5-boronic acid in a pressure tube. The alcohol ester (2.5g, 11mmol) was dissolved in 1,4-dioxane (94mL), and Pd(PPh3)4 (1.1g, 0.95mmol) was added and sodium carbonate solution (9.4 mL, 19 mmol, 2 mol/L), seal the tube, and place it in a methoxypyridine 100°C oil bath for heating. Heating was stopped after 9 hours, and TLC detected that the reaction was complete. Add 50 mL of saturated ammonium chloride solution to quench the reaction. Transfer the reaction solution to a separatory funnel and add 300 mL of EA and 50 mL of saturated saline. After shaking, a flocculent gray solid will precipitate in the middle layer. Filter with suction to separate the gray solid and separate the filtrate. The organic phase and the aqueous phase were extracted twice with 250 mL of EA. The organic phase and the gray solid were combined, spin-dried and subjected to column chromatography. The eluent was EA:PE=4:1-1:1 to obtain 2.7g of a light yellow solid product, which was collected. Rate 100%. Rf=0.35 (PE:EA=1:1). 1H-NMR(MHz, CDCl3)δ8.39(s,1H),8.21(s,1H),8.18(d,1H),8.01(td ,J＝8.3,2.6Hz,1H),7.16(d,J＝1.8Hz,1H),7.12(dd,J＝8.4,2.9Hz,1H),4.11(q,J＝6.9Hz,2H),1.51 (t,J=6.9Hz,3H).
Preparation step 5 of 6-hydroxy-4-(6-fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile: 6-hydroxy-4-( 6-Fluoro-3-pyridine)-pyrazolo[1,5-A]pyridine-3-carbonitrile
Add 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxola) into a 250mL single-neck bottle. Boran-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5g, 23mmol), tetrahydrofuran (120mL), under ice bath conditions, slowly add sodium hydroxide solution (60mL, 120mmol, 2mol/L), hydrogen peroxide (14mL, 140mmol, 30mass%), stir at low temperature. After TLC monitors that the reaction is complete, slowly add sodium thiosulfate solution (50mL, 150mmol, 3mol/L). After returning to room temperature, add water (250mL), extract with EA (250mL×2), and combine the organic phases and wash with 0.1M NaOH solution (500mL ×2). Combine all the water phases, adjust the pH to 4 with dilute hydrochloric acid, stir at room temperature for 15 minutes, and filter with suction to obtain a wet filter cake. Extract the mother liquor with EA (250 mL . All solids were combined and dried at 50°C to obtain 5.1 g of light yellow solid, which was the target product (yield 86.0%). Rf=0.25 (DCM/MeOH=100:1). LCMS: m/z=255.10[M+H]+. 1H NMR(MHz,DMSO)δ10.44-10.37(m,1H),8.54(s,1H),8.49-8.46(m,1H),8.42-8.40(m,1H) ,8.26-8.21(m,1H),7.40-7.35(m,1H),7.32-7.30(m,1H).
References
[1] [Invented in China] CN201911244557.9 RET inhibitor, its pharmaceutical composition and its use
