A kind of preparation method of adenosine receptor antagonist
A solid and compound technology, applied in the field of new heterocyclic compounds, can solve the problems of less antagonists and lower survival rate after treatment
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[0139] When preparation routes are not included, relevant intermediates are commercially available (e.g. from Sigma Aldrich, Alfa)
[0140] general process
[0141] Commercially available reagents were used without further purification. Room temperature means 20-27°C. 1H-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values are expressed in parts per million, ie δ values. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectral results were corrected for background peaks. Chromatography refers to column chromatography using 100 mesh silica gel and done under nitrogen pressure (flash chromatography). TLC used to monitor the reaction refers to TLC performed using the specific mobile phase and silica gel F254 from Merck as stationary phase.
[0142] LC-MS experiments were measured...
Embodiment 1
[0173] Embodiment 1: the preparation of compound 1
[0174]
[0175] Compound 1a (8.0g, 57.9mmol) was dissolved in a mixed solution of dioxane (180mL) and water (5mL), then selenium dioxide (7.07g, 63.7mmol) was added; the reaction temperature was raised to 55 degrees and stirred until Selenium dioxide is completely dissolved. Then the reaction system was stirred overnight at the reflux temperature, and the reaction of the raw materials was detected by thin layer chromatography. The reaction solution was filtered, and the filtrate was concentrated to obtain an oily crude product, which was added to water (120 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain light yellow oily compound 1b (6.5 g, yield: 66%).
[0176] Compound 1b (6.5 g, 38 mmol) was dissolved in ethanol (100 mL), and sodium bicarbonate (8.0 g, 96 mmol...
Embodiment 2
[0195] Embodiment 2: the preparation of compound 45
[0196]
[0197] Chlorosulfonic acid isocyanate (15.5 mg, 0.11 mmol) was added to a solution of compound 1h in dichloromethane (3 mL) at 0°C. The reaction solution was stirred at 0°C for 2 hours, and the reaction of the raw materials was detected by LC-MS. The reaction solution was diluted with dichloromethane (30 mL), and washed with saturated brine (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain a crude product, which was separated by preparative high performance liquid chromatography (5-95% acetonitrile, 0.1% formic acid) to obtain light yellow solid compound 45 (8 mg, yield: 22%). 1 HNMR (500MHz, MeOH-d 4 ):δ7.65-7.58(m,2H),7.34(s,1H),7.31(s,1H),7.21-7.15(m,2H),2.46(s,3H); MS 359.3[M+H] +
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