Nebivolol intermediate crystal and preparing method thereof
A technology of intermediates and crystals, applied in the field of medicinal chemistry, can solve the problems of poor purity, darkening of color, unsuitable for commercial storage, etc., and achieve the effect of good crystallinity and high purity
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[0037] The preparation of the oil of compound (I):
[0038] (a) Preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester
[0039] In a 500ml reactor equipped with mechanical stirring and condenser, add 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid (50g, 255mmol), methanol 394ml and acid methanol (20.3g / 100ml) 6ml, react at about 45°C for 2 hours, cool to room temperature (about 20°C), add NaHCO3 (2.8g, 33.4mmol) and stir for about 1 hour, distill under reduced pressure, add ethyl acetate to the residue 200ml was dissolved, and the organic phase was washed once with 200ml of 2% sodium bicarbonate and once with 200ml of saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness to obtain 52.9 g of an off-white solid. The purity of the product was determined by HPLC, and the content was 99.46% calculated by the area normalization method.
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Embodiment 12
[0044] Example 12-Chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethanone crystal preparation
[0045] Take 4 g of the brown oil obtained in (c) of the above reference example, add 4 ml of methyl tert-butyl ether to it, heat (50° C.) to dissolve, stir and crystallize at about 10° C. for 16 hours. Suction filtration and drying at 40°C to constant weight yielded 2.55 g of an off-white solid. The purity of the product was determined by HPLC, and the content was 95.33% calculated by the area normalization method.
[0046] X-ray powder diffraction pattern see figure 2 , the measurement conditions and measurement data are as follows:
[0047] Instrument: Rigaku D / MAX-2500 X-ray diffractometer
[0048] Target: Cu-Kα ray λ=1.5405A
[0049] Pipe pressure: 40kv
[0050] Pipe flow: 100mA
[0051] Scanning range: 2θ=2-50°
[0052] 2θ
[0053] Among them, 2θ is the position of the diffraction peak, and I is the intensity of the diffraction peak.
Embodiment 22
[0054] Example 22-Chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethanone crystal preparation
[0055] Take 4g of oil, add 2ml of isopropyl ether to it, heat (60°C) to dissolve, stir and crystallize at about 10°C for 6 hours. Suction filtration and drying at 40°C to constant weight yielded 2.76 g of an off-white solid. The purity of the product was determined by HPLC, and the content was 96.56% calculated by the area normalization method.
[0056] The measurement conditions and measurement data of the X-ray powder diffraction pattern are the same as in Example 1.
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