Method for producing oligonucleotide
A manufacturing method and technology of oligonucleotides, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve problems such as scale expansion limitation, difficulty in structural analysis of intermediates, excessive use of reagents and raw materials, etc.
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Embodiment 1
[0665] Embodiment 1 (the synthesis of the nucleoside that is bonded with quasi-solid phase protecting group at 3' position hydroxyl): the synthesis of compound 3
[0666] [chemical formula 58]
[0667]
[0668] Synthesis of Step 1 Compound 2
[0669] To a solution of compound 1 (8.02 g, 22.4 mmol), succinic anhydride (3.35 g, 33.5 mmol) in dichloromethane (80 g) was added triethylamine (6.21 mL, 44.8 mmol) at room temperature under nitrogen atmosphere , stirring for 4 hours and 3 minutes. A 2.0 M phosphoric acid-triethylamine aqueous solution was added to the reaction mixture for liquid separation. The obtained organic layer was washed with 2 M phosphoric acid-triethylamine aqueous solution by two separations, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain compound 2 (11.37 g, Yield 91%).
[0670] 1 H-NMR: (300MHz; CDCl 3 )δ0.13(s, 6H), 0.93(s, 9H), 1.23(t, 9H), 1.92(d, 3H), 2.04-2.13(m, 1H), 2.39-2.46(m, 1H),...
Embodiment 2
[0674] Example 2 (Deprotection of TBS group): Synthesis of Compound 4
[0675] [chemical formula 59]
[0676]
[0677] Under a nitrogen atmosphere, to a solution of compound 3 (2.97 g, 2.2 mmol) in tetrahydrofuran [THF] (65 g) was added a 1.0 M tetrabutylammonium fluoride [TBAF] / THF solution (2.4 mL, 2.4 mmol), stirring for 2 hours and 10 minutes. Methanol was added to the reaction mixture, and the precipitated solid was filtered to obtain Compound 4 (2.66 g, yield 98%) as a white solid.
[0678] 1 H-NMR: (300MHz; CDCl 3)δ0.88(t, 9H), 1.09-1.84(m, 96H), 1.93(d, 3H), 2.30-2.45(m, 2H), 2.62-2.73(m, 4H), 3.82-4.04(m, 9H), 5.02(s, 2H), 5.25-5.29(m, 1H), 6.19(q, 1H), 6.53(s, 2H), 7.49(d, 1H), 8.07(brs, 1H).
Embodiment 3
[0679] Example 3 (H-phosphonation): Synthesis of Compound 5a
[0680] [chemical formula 60]
[0681]
[0682] Under a nitrogen atmosphere, 2,2-dimethylbutyryl chloride (0.33 mL, 2.4 mmol) was added to a solution of phosphorous acid (336 mg, 4.0 mmol) in pyridine (10 mL) at 40° C., followed by stirring for 39 minutes. Compound 4 (498 mg, 0.40 mmol) was added to the reaction mixture, stirred at 40° C. for 1 hour, 2,2-dimethylbutyryl chloride (56 μL, 0.40 mmol) was added, and stirred for 1 hour and 45 minutes. Acetonitrile was added to precipitate a solid, which was cooled with ice and filtered to obtain Compound 5a (562 mg) as a white solid.
[0683] 1 H-NMR: (300MHz; CDCl 3 )δ0.88(t, 9H), 1.16-1.83(m, 96H), 1.92(d, 3H), 2.31-2.35(m, 2H), 2.68(brs, 4H), 3.90-3.98(m, 6H) , 4.17-4.24(m, 3H), 5.02(s, 2H), 5.39(d, 1H), 6.38(q, 1H), 6.53(s, 2H), 6.94(d, 1H), 7.68(d, 1H ).
[0684] 31 P-NMR: (300MHz; CDCl 3 )δ6.54.
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