N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amine → 1-Chloro-N-(4-methoxybenzyl)-N-(thiazol-2-YL)isoquinoline-6-sulfonamide

Participants

Reaction Conditions

Reaction Steps

To a flask containing an ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (0.423 g, 1.922 mmol) in 2Me-THF (7.04 ml) was added lithium bis(trimethylsilyl)amide (2.014 ml, 2.014 mmol) dropwise over 10 min. The mixture was stirred for 15 min prior to the addition of a solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see Example 73, Step 1) (0.750 g, 1.831 mmol) in 2Me-THF (3.5 ml). After 1 hr of stirring (ice melt) LC-MS indicated about 65% conversion to product with starting ester and amine present. The mixture was re-cooled to 0° C. and additional LiHMDS (0.5 eq) was added. The mixture was allowed to stir and slowly warm to room temperature overnight. LC-MS indicated about 90% conversion to desired product. The reaction was quenched by the addition of acetic acid (˜2 ml) and the resulting mixture (some precipitate formation) was dried under reduced pressure and purified with a 40 g silicycle HP column ramping EtOAc in heptane (0 to 50%) providing product 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (0.530 g, 1.188 mmol, 64.9% yield) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.71 (s, 3H) 5.11 (s, 2H) 6.69-6.76 (m, 2H) 7.04 (d, J=3.62 Hz, 1H) 7.26-7.33 (m, 2H) 7.42 (d, J=3.62 Hz, 1H) 7.59-7.64 (m, 1H) 7.85 (dd, J=8.95, 1.81 Hz, 1H) 8.21 (d, J=1.76 Hz, 1H) 8.33-8.41 (m, 2H). m/z (ESI) 446.1 (M+H)+.

Provenance & Evidence