4'-substituted nucleoside reverse transcriptase inhibitors and preparations thereof
a reverse transcriptase inhibitor and substituted nucleoside technology, applied in the field of substituted nucleoside reverse transcriptase inhibitors and preparations thereof, can solve the problems of mutant hiv strains resistant to known inhibitors, high susceptibility to debilitating and ultimately fatal opportunistic infections, and prone to stereochemical erosion
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example 1
Synthesis of (2R,3S,5R)-5-(4-amino-2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (1)
[0200]
Step 1: Synthesis of 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine
[0201]2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 5.32 mmol) was massed into a 250 mL round-bottom flask and dried over P2O5 under vacuum overnight. To this were injected acetonitrile (60 mL) and acetic acid (12 mL) at room temperature, followed by the addition of 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (2.64 g, 7.45 mmol) under argon atmosphere. The mixture was heated to 70° C. and stirred for 36 hours. The resulting mixture was cooled to 25° C., diluted with DCM (150 mL), washed with water (2×50 mL) and brine (2×50 mL) successively. The organic layer was collected, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. silica gel column using ethyl acetate / petroleum ether (0% to 20% Et...
example 2
Synthesis of Ammonium ((2R,3S,5R)-5-(4-amino-2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl Triphosphate (2)
[0223]
Step 1: Synthesis of 2-((4,4,6,6-tetraoxido-1,3,5,2,4,6-trioxatriphosphinan-2-yl)oxy)benzoate
[0224]In a glove box under an argon atmosphere, dry tributylamine (0.4 ml, 1.679 mmol) was added to the flask containing tributylammonium pyrophosphate (112 mg, 0.205 mmol) dissolved in 0.4 mL dimethylformamide (DMF) to give a clear solution. The clear solution was then injected into the flask containing dry 2-chloro-4H-benzo[d][1,3,2]dioxaphosphinin-4-one (27.6 mg, 0.136 mmol) in dimethylformamide (0.4 mL) under vigorous stirring. The resulting mixture was stirred at 30° C. for 30 min to give 2-((4,4,6,6-tetraoxido-1,3,5,2,4,6-trioxatriphosphinan-2-yl)oxy)benzoate which was used to the next reaction directly without any work-up.
Step 2: Synthesis of Ammonium ((2R,3S,5R)-5-(4-amino-2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl...
example 3
Synthesis of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (EFdA) from (2R,3S)-5-acetoxy-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoate
[0226]
Step 1: Synthesis of (2R,3S,5R)-2-ethynyl-5-(2-fluoro-6-((trimethylsilyl)amino)-9H-purin-9-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoate
[0227]To a stirred solution of 2-fluoro-7H-purin-6-amine (4.79 g, 31.3 mmol) in MeCN (210 mL) was added N, O-bis(trimethylsilyl)acetamide (35.3 mL, 144 mmol). The reaction mixture was heated to 81° C. and stirred for 1 hour. The resulting solution was cooled to room temperature and trimethylsilyl trifluoromethanesulfonate (7.84 mL, 43.3 mmol) was added, followed by acetonitrile (105 mL). To the above was added a solution of (2R,3S)-5-acetoxy-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoate (10.5 g, 24.06 mmol) in MeCN (100 mL) over 2 hours. The resulting mixture was stirred...
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