Methanesulfonic acid salt of pyrazolopyrimidine compound, crystal thereof, and process for producing the same
A technology of pyrimidine mesylate and pyrazolo, which is applied in the fields of mesylate of pyrazolopyrimidine compounds, its crystallization and its preparation, and can solve the problems of low total yield, poor industrial productivity, and target product yield Low problems, to achieve the effect of excellent solubility and dispersibility, excellent formulation formation, high crystallization yield
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Embodiment 1
[0206] 1-cyano-1-(2-chloro-4-methoxyphenyl)propan-2-one:
[0207]
[0208] Under argon atmosphere, to 1-bromo-2-chloro-4-methoxybenzene (54g), sodium cyanoacetone (sodium cyanoacetone) (28.2g) and tert-butoxysodium (51.5g) of 1, To the 2-dimethoxyethane (243 mL) suspension was added tetrakis(triphenylphosphine)palladium (7.04 g). The mixture was heated to reflux for 10.5 hours. The reaction mixture was cooled to 25 °C and toluene (21.6 mL) was added. The mixture was stirred for 1 hour at an internal temperature of 20-30°C. The reaction mixture was filtered, and the resulting solid was washed with toluene. The obtained solid was dissolved in a mixed solvent of 2 mol / L hydrochloric acid / toluene, and the mixture was separated. The title compound (300.7 g) in the organic layer was quantified by using the HPLC internal standard method.
[0209] Quantitative value: 71%;
[0210] Yield: 38.7g;
[0211] TLC: Rf 0.29 (n-hexane: ethyl acetate = 3: 1);
[0212] NMR (300MHz, CD...
Embodiment 2
[0214] 1-cyano-1-(2-chloro-4-methoxyphenyl)propan-2-one:
[0215]To a mixture of 1-bromo-2-chloro-4-methoxybenzene (120 g) in diethylene glycol dimethyl ether (230 mL) and 1,2-dimethoxyethane (90 mL) under argon atmosphere To the solution, sodium cyanoacetone (62.6 g), sodium tert-butoxide (114.6 g) and sodium iodide (81.2 g) were added with stirring at room temperature to obtain a suspension. By another procedure, diethylene glycol dimethyl ether (40 mL), palladium acetate (426 mg) and triphenylphosphine (1.99
[0216] The mixture of g) was stirred at 110° C. for about 30 minutes to dissolve it. This solution was dropped into the above suspension. The mixture was heated to an internal temperature of 110-115°C and stirred for 7 hours. The reaction mixture was cooled, diluted with ethyl acetate (480 mL), and washed with aqueous sulfuric acid (concentrated sulfuric acid 101 g / water 660 mL). The organic layer was washed twice with 10% saturated aqueous sodium chloride (360 mL...
Embodiment 3
[0219] 5-amino-3-methyl-4-(2-chloro-4-methoxyphenyl)pyrazole:
[0220] Under an argon atmosphere, to a solution of the compound (38.7 g) prepared in Example 1 in toluene at an internal temperature of 10 to 30° C., acetic acid (14.5 mL) and a 60% aqueous solution of hydrazine hydrate (17.7 mL ). The mixture was stirred at an internal temperature of 45-55°C for 7 hours. To the reaction solution cooled to an internal temperature of 10-30°C, 2 mol / L hydrochloric acid was added, and then the mixture was separated. The pH value of the aqueous layer was adjusted to 6.5-7.5 by adding 25 wt% sodium hydroxide. Isopropyl acetate (216 mL) was added to the pH-adjusted aqueous layer. The separated organic layer was concentrated under reduced pressure. The residue was heated and n-heptane was added. The internal temperature of the solution was cooled to 10-30°C. After precipitation of crystals, the mixture was stirred for 30 minutes. And, n-heptane was added to the solution, and the m...
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