Crystal form of cytarabine 5'-o-l-valine ester hydrochloride and preparation method thereof
A technology of cytarabine and valine ester, which is applied in the crystal form of cytarabine 5′-O-L-valine ester hydrochloride and its preparation field, and can solve the problem of low yield and poor chemical stability Good, difficult to obtain new crystal forms and other problems, to achieve the effect of high purity, crystal form stability and high chemical stability
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[0044] Equipment used and operating conditions
[0045] X-ray powder diffraction instrument: D8-Advance X-ray diffractometer (measurement conditions: radiation source: copper target; 2θ scanning range 3°~60°; step length 0.02° / step; residence time 0.1 second / step; tube pressure = 40KV; pipe flow = 100mA, etc.)
[0046] Infrared spectrophotometer: NICOLET-5700 Fourier Transform Infrared Spectrometer of American Thermoelectric Company (measurement conditions: sample preparation by potassium bromide tablet method; test range: 400cm -1 ~4000cm -1 . )
Synthetic example
[0048] According to the preparation method of cytarabine 5′-O-L-valine ester hydrochloride reported in the patent document CN105273023A, the details are as follows:
[0049] 1) Using commercially available cytarabine as the starting material and absolute ethanol as the solvent, add N,N-dimethylformamide dimethyl acetal (DMF-DMA), heat up to 65°C, and stir for 4 hours , after the reaction, the reaction solution was cooled to room temperature, filtered, the solid was washed with methyl tert-butyl ether, and dried under vacuum at 45°C to obtain intermediate 1;
[0050] 2) Add intermediate 1 into DMF and stir to dissolve, add Boc-L-valine potassium, stir at room temperature for 1 hour, cool down to -10°C ~ -5°C, add ethyl chloroformate dropwise, after the dropwise, heat up React at 0°C for 4 hours, then rise to room temperature for 2 hours, add isopropyl ether, stir and crystallize at 0°C for 2 hours, filter, dissolve the filter cake in chloroform, wash with 15% sodium carbonate s...
Embodiment 1
[0057] Add 20 g of cytarabine 5′-O-L-valine ester hydrochloride crystal form I obtained by the above synthesis example into 400 ml of DMF, stir at room temperature for 14 days, filter, and then air-dry at 60°C to obtain 19.2 g Solid, yield 96%, purity 99.5%.
[0058] Adopt above-mentioned X-ray powder diffraction instrument and infrared spectrophotometer to analyze gained solid respectively under above-mentioned measuring condition, its X-ray powder diffraction collection of patterns and IR collection of illustrative plates are respectively as follows figure 1 , 2 As shown, it was determined to be the crystal form II of cytarabine 5'-O-L-valine ester hydrochloride.
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