反应详情

To a solution of 2-amino-3-chloro-5-trifluoromethoxybenzoic acid (60.5 g, assume 0.22 mol; see step (iii) above) in 1,4-dioxane (1000 mL) was added 6N HCl (750 mL). Some organics oiled out of solution. The dioxane solution was cooled to less than 0° C. (ice-MeOH bath). A solution of sodium nitrite (18.2 g, 0.26 mol) in H2O (250 mL) was added over 15 minutes via an addition funnel. The resulting solution was stirred for 45 min. Hypophosphorous acid (221.5 mL of 50 wt % in H2O, 291.2 g, 2.20 mol) was added slowly via an addition funnel. The solution was stirred at 0° C. for 1.5 hours, then warmed to room temperature (gas evolution observed) and stirred for 18 hours. The crude solution was transferred to a separating funnel and extracted with Et2O (4×). The combined organics were extracted with aqueous NaHCO3 (3×). The basic aqueous layer was cautiously acidified with 6N HCl and extracted with CH2Cl2 (3×). The CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the crude sub-title compound (26.5 g, 46% from 3-trifluoromethoxybenzoic acid) as a solid that was used in the next step without further purification.

1. stirringThe solution was stirred at 0° C. for 1.5 hours
2. stirringstirred for 18 hours
3. extractionextracted with Et2O (4×)
4. extractionThe combined organics were extracted with aqueous NaHCO3 (3×)
5. extractionextracted with CH2Cl2 (3×)
6. dry with materialThe CH2Cl2 extracts were dried (Na2SO4)
7. filtrationfiltered
8. concentrationconcentrated in vacuo