Eletriptan free base with crystal forms, preparing method thereof and applications of the eletriptan free base
A free technology of eletriptan, applied in nervous system diseases, organic chemistry, drug combination, etc., can solve the problems of low yield and purity, and achieve high HPLC purity, high optical purity, and high yield Effect
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Embodiment 1
[0073]
[0074] In 50 g of oily eletriptan free base shown in formula I (prepared according to patent US2005020663A1), add 500 mL of xylene, heat up to 130 °C and stir for 2 hours, slowly cool down to 0 °C, stir for 2 hours, and filter to obtain The product (white powdery solid shown in structural formula I) was dried to a constant weight of 45g, with a yield of 90%. The HPLC purity of the obtained product was 99.2%, and the ee value was 99.5%.
[0075] Wherein, the obtained product is a kind of free base crystal form of eletriptan containing partial amorphous, and its X-ray diffraction is such as figure 1 shown. figure 1 The resulting product is provided with 2θ values of 8.86°, 11.15°, 15.40°, 16.15°, 16.83°, 17.78°, 19.01°, 20.51°, 20.82°, 22.38°, 23.59°, 24.55°, 25.51°, 26.82 There are corresponding diffraction peaks at the positions of °, 27.22°, 28.58°, 30.16°, 31.01°, 31.82°, 33.04°, 35.27°, 36.20° and 38.47°.
[0076] The differential scanning calorimetry (DS...
Embodiment 2
[0078] In the 500mL three-necked flask, add the product prepared in 10g embodiment 1 (i.e. the eletriptan free base white powdery solid shown in the above-mentioned structural formula I), 40mL of acetone, stir to dissolve for 0.5h, add dropwise 120mL of deionized water , the system appeared white turbid, stirred for 2 h, filtered, washed the filter cake with 20 mL of deionized water, and dried by blasting to constant weight to obtain 7.8 g of eletriptan free base product (white powdery solid) with crystalline form, which is the crystal form a, the yield is 78%. The melting point of the obtained product is 103-105°C, the HPLC purity is 99.2%, and the ee value is 99.5%.
[0079] Wherein, the X-ray diffraction pattern of the obtained eletriptan free base with crystal form (crystal form a) is as follows image 3 shown. image 3 Provides Form I at 2θ values of 8.84°, 11.09°, 12.18°, 14.39°, 16.36°, 16.10°, 16.76°, 17.74°, 18.97°, 19.64°, 20.43°, 20.86°, 21.59°, 22.30° , 23.53°, ...
Embodiment 3
[0082]
[0083] To a 2L three-necked flask, add 19.0 g of eletriptan free base with crystal form (crystal form a) prepared in Example 2, add butanone (12.1 g), and stir to dissolve the system. In addition, in the dark, prepare a hydrobutanone bromide solution (mixing 9.2 g of a 48% hydrobromic acid solution with 45 g of butanone). At 25 °C, the butanone hydrobromide solution was added dropwise to the butanone solution of eletriptan free base with crystal form under the condition of avoiding light, and continued to stir for 2 h, filtered, and the filter cake was rinsed with 50 mL of butanone. , obtain the hydrobromide 20.7g of the eletriptan free base with crystal form shown in structural formula II, the yield is 90%, and the HPLC purity of this hydrobromide is 99.5%, ee value is 99.5% .
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