5-Aminophthalide

The synthesis of bromoacetal 6 from phthalimide (7) is shown in FIG. 11. Based on reactions described in the literature, these transformations were carried out on large scale, and some steps were improved. Nitration of 200 g of phthalimide (7) gives 146 g of 5-nitrophthalimide (8). Reduction of 8 by catalytic hydrogenation, according to the literature procedure, is a bottleneck in the synthesis because of the large volume of solvent needed. With a 2 L Parr hydrogenator pressure vessel, 30 g of 8 is converted to 25 g of amine 9. The next step is also a reduction; aminophthalide 10 is obtained quantitatively from 9 by copper-catalyzed reaction with zinc in aqueous base. Steps b and c could be combined by treating 8 with zinc dust and copper(II) sulfate in 2 M aq. sodium hydroxide. This variation, which is not shown in FIG. 11, removes the bottleneck, potentially allowing 100 g of 10 to be prepared in one step from 146 g of 9. The reaction conditions for the steps shown in FIG. 11 are as follows: a) HNO3, H2SO4, 0° C., 56percent ; b) 5percent Pd/C, H2, EtOAc, 97percent ; c) Zn, CuSO4, 6 M NaOH, 5° C. then heated at 70-80° C. 16 h, 100percent ; d) NaNO2, 4 M HBr, followed by CuBr at 0° C.; e) DIBAL, toluene, -42° C.; f) BF3 OEt2, MeOH, RT.A 500 ml single-mouth flask was charged with 39 g of zinc powder (0.6 mol), 32 ml of a 30percent sodium hydroxide solution, and 24 ml of a 0.2percent CuSO4 solution.4-aminophthalimide 20g (0.123mol), the temperature of the ice water bath was maintained at 0 ° C, stirring for 30min, The yellow solid material turned orange, the turbid liquid was green, and then the reaction solution was stirred at 25 ° C for about 20 minutes, then added to 40 ml of water, and placed at 80 ° C for 12 h.After cooling, a greenish gray reaction mixture is obtained;The solid precipitate was filtered off under reduced pressure with a funnel, and then the filtrate was adjusted to pH 2 with concentrated hydrochloric acid to reflux for 2 h;The pH was adjusted to 5 with NaOH, a large amount of a yellow precipitate appeared, which was filtered, washed three times with water and dried at room temperature to give a yellow solid (13.7 g, yield 75.1percent).

Molecular Weight:149.15
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:149.047678466
Monoisotopic Mass:149.047678466
Topological Polar Surface Area:52.3
Heavy Atom Count:11
Complexity:181
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes