Acetic Anhydride → HCID 86588167, compound

HRID 408068Notes

Reaction equation

HRID 408068 reaction equation
[N:1]([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1[N:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])=[N+:2]=[N-:3].[CH3:20][O:21][C:22]1([O:42][CH3:43])[CH:41]=[CH:40][C:25]([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH2:23]1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[CH3:20][O:21][C:22]1([O:42][CH3:43])[CH:41]=[CH:40][C:25]([C:26]([O:11][CH2:10][C@H:7]2[O:6][C@@H:5]([N:12]3[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]3=[O:14])[C@H:4]([N:1]=[N+:2]=[N-:3])[C@@H:8]2[O:9][C:44](=[O:46])[CH3:45])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH2:23]1

Participants

5

Reactant 3

HCID 7918Acetic AnhydrideHCID 16862926929-65-72×HCID 534461344,4-Dimethoxytrityl chloride

Product 1

HCID 86588167HCID 86588167, compoundYield 90.8%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

Starting material was 2′-azido-2′-deoxyuridine prepared according to literature (Verheyden et al., J. Org. Chem. 36:250, 1971), which was 4,4-dimethoxytritylated at 5′-OH with 4,4-dimethoxytrityl chloride in pyridine and acetylated at 3′-OH with acetic anhydride in a one-pot reaction using standard reaction conditions. With 191 mg (0.71 mmole) 2′-azido-2′-deoxyuridine as starting material, 396 mg (0.65 mmol, 90.8%) 5′-O-(4,4-dimethoxytrityl)-3′-O-acetyl-2′-azido-2′-deoxyuridine was obtained after purification via silica gel chromatography. Reduction of the azido group was performed (Barta et al., Tetrahedron 46:587-94, 1990). Yield of 5′-O-(4,4-dimethoxytrityl) 3′-O-acetyl-2′-amino-2′-deoxyuridine after silica gel chromatography was 288 mg (0.49 mmole; 76%). This protected 2′-amino-2′-deoxyuridine derivative (588 mg; 1.0 mmole) was reacted with 2 equivalents (927 mg; 2.0 mmole) N-Fmoc-glycine pentafluorophenyl ester in 10 ml dry DMF overnight at room temperature in the presence of 1.0 mmole (174 μl) N,N-diisopropylethylamine. Solvents were removed by evaporation in vacuo and the residue purified by silica gel chromatography. Yield was 711 mg (0.71 mmole; 82%). Detritylation was achieved by a one hour treatment with 80% aqueous acetic acid at room temperature. The residue was evaporated to dryness, co-evaporated twice with toluene, suspended in 1 ml dry acetonitrile and 5′-phosphorylated with POCl3 and directly transformed in a one-pot reaction to the 5′-triphosphate using 3 ml of a 0.5 M solution (1.5 mmole) tetra(tri-n-butylammonium)pyrophosphate in DMF according to literature. The Fmoc and the 3′-O-acetyl groups were removed by a one-hour treatment with concentrated aqueous ammonia at room temperature and the reaction mixture evaporated and lyophilized. Purification also followed standard procedures by using anion-exchange chromatography on DEAE Sephadex with a linear gradient of triethylammonium bicarbonate (0.1 M-1.0 M). Triphosphate containing fractions, checked by thin layer chromatography on polyethyleneimine cellulose plates, were collected, evaporated and lyophilized. Yield by UV-absorbance of the uracil moiety was 68% or 0.48 mmole.

Workup

  1. customprepared
  2. customreaction conditions

Sources & evidence

ORD record
ord-eb65b3ef1d8a4687ae2fd080ec106f3a
Source dataset
uspto-grants-2014_06
Patent number
US08758995B2

Reaction notes

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