反应详情

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (39.6 mg, 104.0 mmol) in DMF (1.2 mL) were added diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL, 209.4 μmol). The solution was stirred at ambient temperature for 3 hours, when (S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acid ethyl ester mono acetic acid salt (mixture of diastereomers at phosphorus; 104.0 μmol) in DMF (200 μL) was added. The solution was stirred for 30 minutes when complete consumption of the starting materials was observed. An aliquot (66%) of the reaction was purified by silica gel chromatography using MeOH—CH2Cl2 (10-30%), yielding 27.2 mg of crude product. A small amount of the product (10 mg) was repurified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 4.2 mg (26%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, 3H, J=6.9 Hz), 1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51 (m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80 (d, 2H, J=9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) 31P (121.4 MHz, DMSO-d6) δ 29.5, 30.1. MS (m/z) 608.2 [M+H]+.

1. stirringThe solution was stirred for 30 minutes
2. customwhen complete consumption of the starting materials
3. customAn aliquot (66%) of the reaction was purified by silica gel chromatography
4. customyielding 27.2 mg of crude product
5. customA small amount of the product (10 mg) was repurified by RP HPLC on C18 column