Synthesis
The general steps for the synthesis of 5-aminophthalide from 4-amino phthalimide are as follows: first, phthalimide (7) undergoes a bromoacetal reaction to produce compound 6, as shown in Figure 1. According to the literature, these transformations have been carried out on a large scale and some of the steps have been optimized. The specific operation included the nitration of 200 g of phthalimide (7) to obtain 146 g of 5-nitrophthalimide (8). Subsequently, a 2L Parr hydrogenator pressure vessel was used to reduce 30 g of 8 by catalytic hydrogenation to 25 g of amine 9. This step was the bottleneck of the synthesis due to the large amount of solvent required. Next, aminophthalide 10 was quantitatively obtained from 9 by a copper-catalyzed reaction of zinc in an aqueous base.Steps b and c can be combined, i.e., treatment of 8 with zinc powder and copper(II) sulfate in a 2 M NaOH aqueous solution.This modification is not demonstrated in Fig. 1. The one-step preparation of 100 g of 10 from 146 g of 9 may be achieved by eliminating the bottleneck step, as shown in FIG. 11. The steps detailed in FIG. 11 include: a) reaction using HNO3 and H2SO4 at 0 °C in 56% yield; b) 5% Pd/C catalyzed hydrogenation in EtOAc in 97% yield; c) reaction with Zn and CuSO4 in 6 M NaOH at 5 °C. followed by heating at 70-80°C for 16 h in 100% yield; d) treatment with NaNO2 and 4 M HBr at 0°C, followed by the addition of CuBr; e) reaction with DIBAL in toluene at -42°C; f) treatment with BF3-OEt2 and MeOH at room temperature.
References
[1] Tetrahedron, 1998, vol. 54, # 26, p. 7485 - 7496
[2] Patent: US2011/77394, 2011, A1. Location in patent: Page/Page column 15
[3] Archiv der Pharmazie, 1985, vol. 318, # 7, p. 640 - 648
[4] Patent: CN108383833, 2018, A. Location in patent: Paragraph 0012
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 53 - 56
