Nolatrexed dihydrochloride crystal form II and preparation method and application thereof
A technology of lolatrexil hydrochloride and crystal form, which is applied in the field of new crystal forms of compounds, can solve problems such as lolatrexil hydrochloride that have not been seen yet, achieve simple and easy preparation methods, improve stability, and ensure drug safety Effect
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Embodiment 1
[0040] The preparation of embodiment 1 lolatrexex hydrochloride crude product
[0041] Add 5g of lolatrex to a mixed solution of 10ml of water and 40ml of methanol, add 1.0ml of concentrated hydrochloric acid, and heat to dissolve completely. Add tetrahydrofuran dropwise until crystals are precipitated, and then stand for crystallization according to the conventional method and then filter to obtain the crude product of lolatrexil hydrochloride, whose powder X-ray diffraction pattern is shown in figure 2 .
Embodiment 2
[0042] Example 2 Nolatrexex hydrochloride crystal form II and its preparation
[0043] Put 5 g of the crude product of lolatrexex hydrochloride (prepared in Example 1) into a 250 ml four-necked flask, add 37.5 ml of methanol, and stir to form a suspension at a stirring speed of 120 rpm; add 0.25 ml of concentrated hydrochloric acid, raise the temperature to 60 ° C, and keep 45min, to dissolve to clear;
[0044] Adjust the stirring speed to 55rpm, and lower the temperature to 32°C at a rate of 1°C / min. When the bottle wall no longer dissolves crystal grains, grow crystals at a constant temperature for 60 minutes, and then continue to slowly cool down to 20°C at a rate of 0.6°C / min. , keep the crystal for 120 minutes;
[0045] After filtering, the wet powder was vacuum-dried at 35°C and -0.092MP for 6.5 hours to obtain crystal form II of lolatrexex hydrochloride with a purity of 99.4% and a yield of 95%.
[0046] Such as figure 1 As shown, the crystal form II of lolatrexil hy...
Embodiment 3
[0047] Example 3 Nolatrexex hydrochloride crystal form II and its preparation
[0048] Put 5 g of the crude product of lolatrexil hydrochloride (prepared in Example 1) into a 250 ml four-necked flask, add 30 ml of methanol, stir to form a suspension at a stirring speed of 50 rpm; add 0.15 ml of concentrated hydrochloric acid, heat up to 50°C, and keep for 30 min , to dissolve to clear;
[0049] Adjust the stirring speed to 50rpm, and reduce the temperature to 25°C at a rate of 0.5°C / min. When the bottle wall appears undissolved grains; grow crystals at a constant temperature for 60 minutes, and then continue to slowly cool down to 15°C at a rate of 0.4°C / min. , keep the crystal for 90 minutes;
[0050] After filtering, the wet powder was vacuum-dried at 34°C and -0.088MP for 6.5 hours to obtain crystal form II of lolatrexil hydrochloride with a purity of 99.2% and a yield of 92%.
[0051] Such as figure 1 As shown, the crystal form II of lolatrexil hydrochloride is determin...
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