Modified nucleoside phosphoramidites
A technology of oligonucleotides and nucleobases, applied in the field of modified nucleoside phosphoramidites
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Embodiment 1-4
[0072]
[0073] Following the chemical transformations shown in Schemes 1, 2, 3, 4 and 5, appropriately protected 2'-O-methoxyethyl-3'-aminonucleoside-5'-phosphoramidite building blocks were prepared (executed Examples 1, 2, 3 and 4).
[0074] plan 1
[0075]
[0076] Scheme 1 discloses the synthesis of the uracil base 3'-NH-MMTr-2'-O-methoxyethylphosphoramidite (such as Example 1). The key 3'-azido-2'-methoxyethyl intermediate 3-3 was obtained in low yield via anhydrous intermediate 3-2.
[0077] Due to the low-yield alkylation, 3-1 was reacted with BOMCl / DBU to give the N-3 protected intermediate 3-4, which was obtained by using 2-bromoethyl methyl ether / Ag 2 O / NaI / DMF alkylation to give 2'-O-methoxyethyl derivatives 3-5. Using hydrogenation conditions (Pd / C / H 2 ) deprotection of the N-3-BOM group resulted in 10%-20% of the desired 3'-amino intermediate 3-6a, along with a significantly overreduced by-product 3-6b.
[0078] Scenario 2
[0079]
[...
Embodiment 2
[0091]
[0092] 2'-O-Methoxyethoxy-NH-benzoyl-cytosine phosphoramidite compound 5-4 obtained by conversion of uridine intermediate 4-8 to the 3'-aminocytidine analog 5-1 , followed by phosphorylation using known procedures to give the desired 2'-O-methoxyethoxycytidine phosphoramidite monomer 5-4, as shown in Scheme 3 below.
[0093] Option 3
[0094]
[0095] Preparation of intermediate (5-1) : To a solution of 4-8 (18.50 g, 27.30 mmol) in acetonitrile (250.00 mL) was added TPSCl (16.49 g, 54.60 mmol) and DMAP (6.67 g, 54.60 mmol), then TEA (5.52 g, 54.60 mmol) was added to the solution mmol, 7.56 mL). The reaction mixture was heated under N 2 Stir at room temperature for 5h. Will NH 4 OH (50.00 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 12h. The solution was concentrated and extracted with EA. The organic layer was washed with brine, and washed with Na 2 SO 4 dry. The organic layer was concentrated and purified ...
Embodiment 3
[0100]
[0101] Synthesis of 2'-O-methoxyethyladenosine analogs 6-10 was achieved as shown in Scheme 4 below. Intermediate 6-2 under alkaline conditions (NH 3 / MeOH) afforded diol 6-3, which, after protection of the 5'-hydroxyl group using TBDPSCl, gave 6-4. (Intermediate 6-4.) Then, 6-42'-O was alkylated using 2-bromoethylmethyl ether / NaH / DMF to give the 2'-O-methoxyethyl derivative 6 -5, without the protection of the C-6-exocyclic amine of 6-4. The inventive method of selective alkylation of 2'-OH group of intermediate 6-4 was realized.
[0102] Option 4
[0103]
[0104] Reduction of the 3'-azido group of intermediate 6-5 to amine 6-7, which is then immediately protected, such as with 4-monomethoxytriphenylchloromethane to react with TBAF / THF on the 5' Deprotection of the -OTBDPS group gives precursors 6-8. Phosphorylation of 6-9 was performed using known procedures to give the desired 2'-O-methoxyethoxyadenine-NH-benzoylphosphoramidite monomers 6-10....
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