trk inhibitor, its preparation method and use
A dosage form and compound technology, applied in the field of medicine, achieves the effects of high product yield, mild reaction conditions and simple preparation method
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preparation example 1
[0104]
[0105] Intermediate 2: 6-fluoropyrazolo[1,5-a]pyrimidine-5,7-diol
[0106]
[0107] Under the protection of nitrogen, 2.0 g (24.1 mmol) of raw material 1a, 4.3 g (24.1 mmol) of raw material 1b and 7.3 g (48.2 mmol) of DBU were dissolved in 40 mL of 1,4-dioxane, and reacted at 110 ° C for 18 Hour. TLC detection, after the reaction, concentrated by rotary evaporation, added 20mL of ice water, under the protection of nitrogen, added about 14mL of 5M HCl to adjust the pH value of the solution to about 2, precipitated solid, stirred at low temperature, suction filtered, and vacuum-dried to obtain 2.27g of the product , gray solid, yield 55.7%. LC-MS: 168[M-1] + , t R = 0.416 min.
[0108] Intermediate 3: 5,7-Dichloro-6-fluoropyrazolo[1,5-a]pyrimidine
[0109]
[0110] Under nitrogen protection, 2g (11.8mmol) of intermediate 2 was dissolved in 20mL of phosphorus oxychloride, and then 2mL of N,N-dimethylaniline was added, the temperature was raised, and the rea...
Embodiment 1
[0126] Example 1: (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-6-fluoropyrazolo[1,5-a ]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
[0127]
[0128]Under the condition of nitrogen protection, 60 mg (0.18 mmol) of intermediate 8 and 29 mg of CDI were dissolved in 3 mL of 1,2-dichloroethane, and the temperature was raised to 65° C. to react overnight. Then 16 mg (0.18 mmol) (S)-3-pyrrolidinol (raw material 8a, dissolved in a small amount of 1,2-dichloroethane) and a drop of triethylamine were added, and the reaction was continued overnight at 65°C. TLC detection, after the reaction was completed, concentrated by rotary evaporation, and purified on a silica gel preparation plate (eluent DCM:MeOH=20:1) to obtain 16 mg of the product, a white solid, with a yield of 19.9%. LC-MS: 447.2[M+1] + , t R = 2.101 min.
[0129] 1 H NMR(400MHz,DMSO)δ9.98(s,1H),8.93(d,J=8.3Hz,1H),7.84(s,1H),7.29–6.98(m,4H),5.52(s,1H) , 4.97 (d, J=3.1Hz, 1H), 4.16–4.01 (m, 1H), 3.90–3.7...
preparation example 2
[0131]
[0132] Intermediate 22: 5-Bromo-3-nitropyrazolo[1,5-a]pyridine
[0133]
[0134] Suspend 200 mg of compound 21 in 1 ml of sulfuric acid and cool to 0°C. Add 0.5ml of sulfuric acid / 0.5ml of nitric acid mixture dropwise, and stir at 0°C for 30 minutes. TLC detection, after the reaction, poured into ice water, stirred for 10 minutes, and suction filtered to obtain 160 mg of white solid. used directly in the next reaction.
[0135] Intermediate 23: (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyridine
[0136]
[0137] 160 mg (0.66 mmol) of compound 22, 140 mg (0.629 mmol) of compound 6a, 243 mg (1.89 mmol) of DIEA were dissolved in 5 mL of NMP, and reacted at 150° C. for 5 hours. TLC detection, after the reaction is over, add water and ethyl acetate to stir, let stand, separate layers, extract the aqueous phase with ethyl acetate, combine the organic phases to dry, and spin dry to obtain 0.7g of crude brown oil, which is directly used i...
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