Hexamethyldisilazane → 8-Methyladenosine

HRID 471361Notes

Reaction equation

HRID 471361 reaction equation
Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].O=[CH:22][C@@H]([C@@H]([C@@H](CO)O)O)O.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Al](C)C>[Pd]>[CH3:22][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]

Participants

7

Reactant 5

HCID 13838HexamethyldisilazaneHCID 965448-BromoadenosineHCID 5311110Aldehydo-D-riboseHCID 6097028Ammonium SulfateHCID 16682925Trimethylaluminum

Product 1

HCID 1715558-Methyladenosine

Reagents, catalysts & solvents 1

HCID 23938PalladiumCatalyst

Procedure

Starting with commercially available 8-bromoadenosine (1), the hydroxyl groups of the ribose moiety were transiently protected by treatment with hexamethyldisilazane and catalytic ammonium sulfate. The crude intermediate underwent palladium catalyzed coupling reaction with trimethylaluminum to install the methyl group at the 8-position. The product, without purification, was deprotected directly to afford 8-methyladenosine derivative (2). Treatment of 2 with thionyl chloride in pyridine afforded the chloride derivative 3, which was subjected to reaction with excess methylamine under microwave irradiation to yields the amine 4. Allylic displacement with cis-1-(t-butoxycarbonylamino)-4-chloro-2-butene under catalytic halide exchange conditions proceeded to form amine 5, which was then deprotected with methanolic hydrogen chloride and purified by silica gel chromatography to afford the final product.

Workup

  1. customThe product, without purification

Sources & evidence

ORD record
ord-a2e020e8cb654c3da1af151191af7df5
Source dataset
uspto-grants-2014_01
Patent number
US08633168B2

Reaction notes

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