Chlorosuccinimide → 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine

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Reaction Steps

A portion of the 1-[3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (5.5 g) in dry tetrahydrofuran (50 ml) was added dropwise to a stirred solution of lithium hexamethyldisilazide in tetrahydrofuran (33 ml, 1M solution in tetrahydrofuran) at -78° C. under an atmosphere of nitrogen. After 30 minutes the resulting solution was rapidly transferred, under an atmosphere of nitrogen, into a stirred solution of N-chlorosuccinimide (1.6 g) in dry tetrahydrofuran (50 ml). The resulting mixture was cooled in an ice bath under an atmosphere of nitrogen. The mixture was allowed to warm to room temperature over a period of 20 minutes and was quenched upon an addition of an excess of saturated aqueous potassium dihydrogen orthophosphate. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a residue. The residue was dissolved in ethyl acetate, washed with water and then brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a foam which was chromatographed on silica gel using a mixture of methanol:dichloromethane (2:23) as an eluent to yield 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[ (1,1-dimethylethoxy)carbonyl]-L-histidine (2.85 g) as a mixture of diastereoisomers, (δ (CDCl3) 1.45 (9H, s), 1.48 (9H, s), 3.01 (2H, bd, J=15Hz), 3.23 (2H, bd, J=15Hz), 4.35 (2H, bs), 4.62 (2H, bt, J=17Hz), 4.86 (2H, bt, J=17Hz), 5.48 (2H, m, 4 lines), 6.38 (1H, bs), 6.57 (3H, m), 6.98 (2H, dd, J=9Hz and 2Hz), 7.42 (2H, m), 7.46 (5H, s), 7.49 (5H, s), 7.56 (1H, bs) and 7.60 (1H, bs)), having the formula: ##STR33##

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