Tetrahydrofuran → 5'-(1,4-Dihydro-1-methyl-3-pyridinylcarbonyl)-3'-azido-3'-deoxythymidine
Reaction equation
N1[CH:5]=NN=N1.[CH2:6]([N:8]([CH2:12]C)P([O-])[O-])C.[N:14]([C@@H:17]1[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19]([N:24]2[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]2=[O:26])[CH2:18]1)=[N+:15]=[N-:16].[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:31][C:30]1[C:28](=[O:29])[NH:27][C:25](=[O:26])[N:24]([C@@H:19]2[O:20][C@H:21]([CH2:22][O:23][C:37]([C:36]3[CH2:35][CH:34]=[CH:5][N:8]([CH3:12])[CH:6]=3)=[O:33])[C@@H:17]([N:14]=[N+:15]=[N-:16])[CH2:18]2)[CH:32]=1Participants
Procedure
1-H-tetrazole (462 mg, 6.60 mMoles) was added to 2.00 grams of the N,N diethylphosphoramidite (Structure 6) and to 3'azido-3'deoxythymidine (707 mg, 2.63 mMoles) in 10 ml of anhydrous tetrahydrofuran. (The AZT provided by Aldrich contained 0.085 moles water per mole of AZT.) After 1.5 hours the solution was cooled to -40° C. and a solution of 3-chloroperoxybenzoic acid (873 mg, 4.3 mMoles as 85% reagent) in 15 ml of dry methylene chloride was added rapidly in a dropwise fashion. External cooling was removed and after 15 minutes, 20 ml of 10% aqueous NaHSO4 was added and stirred vigorously for 10 minutes. The mixture was transferred to a separatory funnel with the addition of 50 ml of methylene chloride. Upon shaking an intractable emulsion was formed. After the addition of 500 ml of diethyl ether a clean phase separation was obtained. The organic phase was washed with 30 ml of 10% aqueous NaHSO4, saturated NaHCO3 (25 ml×2), and water (25 ml×2). The organic phase was then dried over sodium sulfate, filtered and dried exvacuo to yield 2.30 grams of crude product. The desired product was then purified by silica gel chromatography with CHCl3 /methanol 99:1 as eluant. 821 mg of product was obtained which was pure by TLC. NMR revealed a mixture of diastereomers. FAB mass spectroscopy revealed a molecular weight of 815.7 In an attempt to separate the d-l pair form the meso pair of isomers the sample was rechromatographed on a longer silica column and eluted with CHCl3 /methanol 99:1. This second chromatography was unsuccessful and complicated by the appearance of a hydrocarbon peak noted on NMR. This hydrocarbon peak was traced to a contaminant present in a commercially obtained reagent grade chloroform. The sample accordingly was subjected to a third chromatographic purification on a 3 inch silica column which was eluted with chloroform followed by CHCl3 /methanol 99:1. This removed all detectable traces of the hydrocarbon contaminant. 260 mg of product was isolated. This material was pure on TLC and by high field NMR. No AZT was noted on HPLC examination of a sample obtained after the first of the three chromatographic separation described above. The proton NMR revealed the presence of diastereomers. Two pairs of isomers were separated by HPLC on silica. However, attempts to further resolve the mixture were unsuccessful. p31NMR demonstrated that 2 phosphorous peaks in each mixture of diastereomers. The structure was further confirmed by proton NMR COSY analysis. High resolution mass spectrometry revealed a molecular weight of 815.2440 (+/-0.0043). This is in agreement with the calculated mass of 815.248. The 300 MHZ NMR is shown in FIG. 2.
Sources & evidence
- ORD record
- ord-2ec7ba75897d451cb25e58e9b18b9ca8
- Source dataset
- uspto-grants-1998_08
- Patent number
- US05789608
Reaction notes
Loading…