Pyrimidine antitumor compound with Hedgehog antagonist activity
A hedgehog pathway and compound technology, applied in the field of pyrimidine anti-tumor compounds, can solve the problems of tumor metastasis and regeneration with little efficacy, and achieve the effect of blocking metastasis and regeneration and inhibiting abnormal cell growth.
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[0052] Example 1
[0053] This embodiment provides an anti-tumor compound A1, the synthesis method of the compound is as follows:
[0054]
[0055] 1) Synthesis of intermediate A1-2:
[0056] Dissolve 4-tert-butoxycarbonylpiperidone (A1-1, 10g, 50.2mmol) in 40 ml of N,N-dimethylformamide, add N,N-dimethylformamide dimethyl while stirring Acetal (6g, 50mmol), after the addition is complete, react at 80°C for 12 hours. Cooled to room temperature, added to ethyl acetate (150mL) and water (50mL), the organic phase was washed twice with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain an orange crude product (13g) directly Cast the next response.
[0057] 2) Synthesis of intermediate A1-3:
[0058] At room temperature, hemimethylthiourea sulfate (6.98g, 25.1mmol) and sodium ethoxide (3.28g, 40mmol) were dissolved in 40ml of ethanol, and after stirring for half an hour, the intermediate A1-2 synthesized in the previous step (13g, 50.2m...
Example Embodiment
[0070] Example 2
[0071] This embodiment provides an anti-tumor compound A2, and the synthesis method of the compound is as follows:
[0072]
[0073] 1) Synthesis of intermediate A2-1:
[0074] A1-4 (1g, 3.19mmol) and ethylamine aqueous solution (71%, 1mL, 15.8mmol) were dissolved in ethanol (10mL) with stirring, heated to reflux, after 12 hours, cooled to room temperature, and spin off under reduced pressure The solvent and concentrate are purified by column chromatography (mobile phase is petroleum ether: ethyl acetate=4:1) to obtain a white solid (400mg, 45%).
[0075] 2) Synthesis of intermediate A2-2:
[0076] Dissolve A2-1 (400mg, 1.44mmol) in a small amount of dichloromethane, add a saturated ethyl acetate solution (3mL) of hydrogen chloride, stir at room temperature for 3 hours, spin off the solvent under reduced pressure, and add the concentrate to a saturated aqueous sodium bicarbonate solution (5mL) and dichloromethane (20mL), the organic phase was washed with saturated b...
Example Embodiment
[0080] Example 3
[0081] This embodiment provides an anti-tumor compound A3. The synthesis method of the compound is as follows:
[0082]
[0083] 1) Synthesis of intermediate A3-1:
[0084] A1-4 (1g, 3.19mmol) and cyclopropylamine (300mg, 5.26mmol) were dissolved in ethanol (10mL) with stirring, heated to reflux, after 12 hours, cooled to room temperature, and the solvent was removed under reduced pressure. The concentrate Refined by column chromatography (mobile phase is petroleum ether:ethyl acetate=4:1) to obtain a white solid (460mg, 50%).
[0085] 2) Synthesis of intermediate A3-2:
[0086] Dissolve A3-1 (460mg, 1.58mmol) in a small amount of dichloromethane, add a saturated ethyl acetate solution (3mL) of hydrogen chloride, stir at room temperature for 3 hours, spin off the solvent under reduced pressure, and add the concentrate to a saturated aqueous sodium bicarbonate solution Wash (5mL) and dichloromethane (20mL), wash the organic phase with saturated brine (10mL), dry and ...
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