Efficient preparation method of fluorine [< 18 > F] safinamide and application of PET imaging agent
A PET imaging agent, safinamide technology, applied in the field of nuclear medicine, can solve the problems of long cycle, high consumption, and difficulty in approving applications in other disease fields
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Embodiment 1
[0059] 3A (615 mg, 1.5 mmol) was dissolved in dry tetrahydrofuran (10 mL), then sodium hydride (60% in mineral oil, 132 mg, 3.3 mmol) was added dropwise to the solution at 0 °C and stirred for 1 h. The reaction mixture was heated to 25°C, di-tert-butyl dicarbonate (1.63 g, 24 mmol) was added slowly, and the mixture was stirred for a further 2 hours. Finally, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic solution was then washed sequentially with water, 1M HCl and brine and the organic portion was collected, the final organic solution was dried over Na2SO4, filtered and concentrated. The product was finally purified by silica gel column chromatography (5-50% ethyl acetate / petroleum ether) to give a colorless solid (4A, 170 mg, 0.28 mmol, 68% yield). 1 H NMR (400MHz, Chloroform-d) δ 7.67 (d, J=1.8Hz, 1H), 7.54 (dt, J=7.8, 1.5Hz, 1H), 7.26 (dd, J=7.8, 1.5Hz, 1H) ,7.13–6.96(m,3H),6.80(dd,J=8.3,4.6Hz,2H),4.86(s,2H),4.69–3.70(m,3H),1.33...
Embodiment 2
[0061] Similarly, the production of 4B only needs to replace the equimolar amount of 3A in Example 1 with 3B, and the rest of the operations are the same, and finally a colorless oily substance 4B can be obtained. 1 H NMR (400MHz, Chloroform-d) δ 7.59 (t, J=1.8Hz, 1H), 7.46 (dt, J=7.9, 1.6Hz, 1H), 7.34 (dt, J=7.8, 1.3Hz, 1H) ,7.25(p,J=4.8Hz,3H),6.99-6.88(m,2H),5.01(s,2H),4.90-3.89(m,3H),1.71(d,J=2.8Hz,2H), 1.46(d,J=4.3Hz,18H),1.34(d,J=7.0Hz,3H),1.31–1.22(m,1H).
[0062] Wherein the preparation of 3A / 3B can be obtained based on the prior art, and a preparation method thereof is such as figure 2 The starting compounds are shown in 1A / 1B.
[0063] ②Synthesis of precursor Mel-SF, SPIAd-SF, SPI5-SF
[0064] Compound 4A (1 equiv.) and m-chloroperoxybenzoic acid (1 to 2 equiv.) were dissolved in an anhydrous organic solution (such as tetrahydrofuran, dichloromethane, N,N-dimethylformamide, etc.) with stirring, at 40 °C Stir at 80°C for 1 hour to 6 hours. The reaction mixture wa...
Embodiment 3
[0066]In a closed reaction vial, compound 4A (1 equiv) was stirred with 85% m-chloroperoxybenzoic acid (1.1 equiv) in dichloromethane (DCM) at 40°C for 80 minutes. After cooling to room temperature, KOH (7 equiv.) and Mylbauer's acid (1.3 equiv.) were added and stirred for a further 45 minutes. The reaction mixture was then diluted with DCM and filtered through filter paper. The solvent of the collected organic phase was removed under reduced pressure at 35°C until the first solid precipitated. Then, hexane was added slowly and the mixture was left to stand at -20°C for 12 hours to complete the precipitation. The solid was collected by filtration, washed with n-hexane, and dried in air and vacuum. Finally, the crude product was purified by silica gel column chromatography (SiO2, 40-100% ethyl acetate / petroleum ether) to obtain the Mel-SF precursor.
[0067] Mel-SF (41% yield, white solid): 1 H NMR (400MHz, Chloroform-d) δ7.86-7.76(m,1H), 7.69-7.57(m,1H), 7.47-7.36(m,1H), 7...
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