Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor
A CH3, -5-N technology, applied in antiviral agents, medical preparations containing active ingredients, organic chemistry, etc.
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Embodiment 13
[0013] Preparation of Example 13-oxo-4-(3,5-dimethyl)-phenylbutyric acid ethyl ester (compound 1)
[0014] Suspend the activated zinc powder (washed successively with 3N hydrochloric acid, distilled water, absolute ethanol, and absolute ether, and then vacuum-dry) in dry THF (125ml) and heat to reflux, drop 20 drops of ethyl bromoacetate , when the cloudy solution was gray-green (about 45 minutes), 3,5-dimethylbenzonitrile (1.305 g, 9.0 mmol) was added in one portion, and bromoacetic acid was slowly added dropwise in about 1 hour Ethyl ester (4.95ml, 45mmol), reflux for 10 minutes after the dropwise addition. Diluted with THF (125ml×3), added potassium carbonate aqueous solution (50%, 54ml) and stirred rapidly for 45 minutes, left to stand and separated to form two phases. The upper THF phase was poured out, and the remaining part was washed with THF (2×100 ml). The combined THF phases were added with hydrochloric acid (10%, 50 ml) and stirred at room temperature for 45 minut...
Embodiment 2
[0016] Preparation of Example 22-thio-6-(3,5-dimethyl)-benzyluracil (compound 2)
[0017]4.54g (197.5mmol) of sodium metal was dissolved in 108ml of absolute ethanol, 10.54g (136mmol) of thiourea and 2.10g (9.0mmol) of compound 1 were added, and the reaction mixture was heated to reflux for 6 hours. Rotate under reduced pressure at 40-50°C until almost completely dry, and dissolve the residue in water (80ml). Add concentrated hydrochloric acid (20ml) to precipitate a precipitate, add glacial acetic acid to adjust pH ≈ 4, filter the precipitate with a suction filter funnel, wash with 10% EtOH solution, and dry to obtain a white solid 2-thio-6-(3,5-di Methyl)-benzyluracil 2.098g (compound 2), two-step total yield 94.7%, mp 253~255°C.
[0018] MS(ESI+) m / z: 247.1[M+H] + , 269.1[M+Na] +
Embodiment 3
[0019] Preparation of Example 36-(3,5-dimethyl)-benzyluracil (compound 3)
[0020] 2-Thio-6-(3,5-dimethyl)-benzyluracil (2.098g, 8.53mmol) was dissolved in 10% chloroacetic acid (150ml), and heated to reflux for 24 hours. After cooling to room temperature, a white needle-like solid precipitated, which was filtered out with a suction filter funnel, washed with cold ethanol and cold ether in turn, and dried to obtain a white solid 6-(3,5-dimethyl)-benzyluracil 1.258g, yield 64.2%, mp 288-290°C.
[0021] MS(ESI+) m / z: 231.1[M+H] + , 253.1[M+Na] +
[0022] 1 H NMR (300MHz, DMSO-d 6 )δ: 11.69(s, 1H, N3-H), 10.93(s, 1H, N1-H), 6.92~6.90(m, 3H, Ph-H), 5.22(s, 1H, C5-H), 3.54 (s, 2H, CH 2 ), 2.25(s, 6H, Ph-CH 3 ).
[0023] 13 C NMR (75MHz, DMSO-d 6 )δ: 21.31 (CH 2 Ph), 37.90 (CH 2 Ph), 99.24(C-5), 156.18(C-6), 152.07(C-2), 164.57(C-4), 138.00, 136.38, 128.84, 127.19(C arom ).
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