反应 #1876832

反应方程式

p-bromophenol

triethylamine

phosphoryl chloride

→

4c

p-Bromophenyl phosphorodichloridate

溶剂

Et2O

Et2O

反应条件

后处理

1. 1
   温度heated
2. 2
   温度to reflux for two hours
3. 3
   温度The reaction mixture was cooled to room temperature
4. 4
   过滤filtered under aspirator pressure
5. 5
   洗涤The precipitate was washed with anhydrous Et2O (2×50 mL)
6. 6
   其他The combined Et2O layers were evaporated to dryness on rotary evaporator

实验过程

Following the procedure described by McGuigan et al., 1993, Supra, a solution of p-bromophenol (13.20 g; 76.30 mmol) and distilled triethylamine (10.65 mL) in anhydrous Et2O (165 mL) was added dropwise into a vigorously stirred solution of phosphoryl chloride (8.5 mL; 91.2 mmol) in anhydrous Et2O (83 mL) at 0° C. over a period of three hours under nitrogen atmosphere. Subsequently, the resultant mixture was gradually warmed up to room temperature, stirred efficiently overnight at room temperature and then heated to reflux for two hours. The reaction mixture was cooled to room temperature and filtered under aspirator pressure. The precipitate was washed with anhydrous Et2O (2×50 mL). The combined Et2O layers were evaporated to dryness on rotary evaporator to yield crude 4c as a pale yellow oil which was then subjected to vacuum distillation to give pure 4c (14.05 g; 63.5% yield) as a colorless viscous oil (bp. 110–115° C./2 mm Hg). IR (Neat) 3095, 1481, 1303, 1187, 948, 829 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.50 (2H, d, J=9.0 Hz), 7.15 (2H, d, J=9.0 Hz). GC/MS (m/e) 290 (M+), 254 (M+−Cl), 173 (M+−POCl2, 81Br), 171 (M+−POCl2, 79Br), 156 (M+−PO2Cl2, 81Br), 154 (M+−PO2Cl2, 79Br). p-Bromophenyl methoxyalaninyl phosphorochloridate 5c. Following the procedure described by McGuigan et al., Supra, a solution of distilled triethylamine (8.80 mL; 63.14 mmol) in anhydrous CH2Cl2 (180 mL) was added dropwise via an addition funnel into a vigorously stirred solution of p-bromophenyl phosphorodichloridate 4c (8.69 g; 29.97 mmol) and L-alanine methyl ester hydrochloride (4.19 g; 30.02 mmol) in anhydrous CH2Cl2 (250 mL) at −70° C. over a period of three hours under nitogen atmosphere. Subsequently, the resultant mixture was allowed to gradually warm up to room temperature and stirred overnight at room temperature. The solvent was removed on rotary evaporator. Anhydrous Et2O (300 mL) was added to dissolve the residue and then filtered under aspirator pressure to remove the white solid. The white solid was rinsed with anhydrous Et2O (2×60 mL). The Et2O layers were combined and evaporated to dryness to afford a quantitative yield of 5c (10.7 g) as a pale pink-yellow viscous oil. This product was then used for the next step reaction without further purification. IR (Neat) 3212, 2989, 2952, 1747, 1483, 1270, 1209, 1147, 927, 831, 757 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.70 (1H, br, Ala-NH), 7.48 (2H, d, J=9.0 Hz, aryl H), 7.16 (2H, d, J=9.0 Hz, aryl H), 3.79 & 3.77 (3H, s & s, —OCH3), 1.51 & 1.40 (3H, d & d, Ala-CH3). MS (CI, m/e) 357.9 (M+, 81Br), 355.9 (M+, 79Br), 322.0 (M+−Cl, 81Br), 320.0 (M+−Cl, 79Br), 297.9 (M+−COOCH3, 81Br), 295.9 (M+−COOCH3, 79Br), 184.0 (M+−BrC6H4O). Characterization data of phenyl methoxyalaninyl phosphate derivatives of AZT 1, d4T 2 and 3dT 3: HPLC was conducted by using C18 4×250 mm LiChrospher column eluted with 70:30 water/acetonitrile at the flow rate of 1 ml/minute. The purity of the following compounds exceed 96% by HPLC. 13C NMR peaks labeled by asterisks were split due to diastereomers arising from the phosphorus stereocenters.

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