Polycrystalline type forms of 2-aminopyrimidine compound
A technology of compounds and crystal forms, applied in the field of medicinal chemistry, can solve the problems such as the clinical pressure of drug resistance and the side effects of wild-type cytotoxicity.
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preparation example Construction
[0167] The preparation of the compound of formula (I) is as follows:
[0168]
[0169] 2,4,5-Trichloropyrimidine (9g, 49mmol), 2-naphthylamine (7.38g, 51.6mmol), sodium carbonate (10.41g, 98.1mmol) were dissolved in absolute ethanol (150mL), and stirred overnight at room temperature. Ice water (450 mL) was added with stirring, and a large amount of solid precipitated out. Filter under reduced pressure and dry in vacuo to obtain brown solid compound Int-01 (12.57 g, yield 88%).
[0170]Add 2,5-dichloro-N-(naphthalene-2-yl)pyrimidin-4-amine (Int-01, 10.00g, 34.4mmol), 2-methoxy-4-fluoro-5- Add anhydrous isopropanol (115 mL) to nitroaniline (6.41 g, 34.4 mmol), p-toluenesulfonic acid monohydrate (7.86 g, 41.3 mmol), and reflux overnight at 83°C. After the reaction, the reaction solution was cooled to room temperature, filtered, and a mixture of ammonia (5.8 mL) and water (50 mL) was added to the solid, stirred for 2 to 3 hours, filtered, washed with water (25 mL), and dried ...
Embodiment 1
[0230] Embodiment 1: the preparation of crystal form I
[0231] Method 1: Dissolve 1 g of the crude compound of formula (I) in 30 ml of ethyl acetate at 60°C, add 30 ml of methyl tert-butyl ether, cool to room temperature, stir overnight, filter, and dry to obtain Form I.
[0232] Method 2: Dissolve 1 g of the crude compound of formula (I) in 30 ml of acetone, stir for 2 hours, place in a refrigerator at 4°C overnight, filter, and dry to obtain Form I.
[0233] The XRD pattern of obtained crystal form I is shown in figure 1 , the diffraction angle data are basically shown in Table 1 below. The TG spectrum of crystal form I is basically as figure 2 shown. The DSC spectrum of crystal form I is basically as image 3 shown.
[0234] It can be seen that the crystal form I is an anhydrous, diamond-shaped block crystal with a melting point of about 177.68°C, no crystal transformation behavior before melting, and begins to decompose at about 250°C. The DVS experiment shows that...
Embodiment 2
[0238] Embodiment 2: the preparation of crystal form II
[0239] Method 1: Take 1 g of the crude compound of formula (I) and dissolve it in a mixed solvent of methanol and water (20 ml, 1:1) at 50°C, cool down and stir for crystallization, filter, and dry to obtain crystals.
[0240]Method 2: Take 1 g of the crude compound of formula (I) and dissolve it in a mixed solvent of acetonitrile and water (30 ml, 2:1) at 50°C, cool down and stir for crystallization, filter, and dry to obtain crystals.
[0241] The XRD pattern of obtained crystal form I is shown in Figure 4 , the diffraction angle data are basically shown in Table 2 below. The TG spectrum of crystal form II is as follows Figure 5 shown. The DSC spectrum of crystal form II is as follows Figure 6 shown.
[0242] It can be seen that the crystal form II is a dihydrate, a columnar crystal. It begins to lose water and weight at about 80°C when it is heated, and loses two molecules of water at 150°C and turns into a c...
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