Molecules 2020, 25, 468
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The main reagents including SM01 and SM02 were provided from Aikon International Ltd.
(Nanjing, China). Their purities were controlled to be higher than 99%, the content of maximal single
impurity was limited to be less than 0.5%. NBS was purchased from Shanghai Hanhong Chemical, Co.,
Ltd. (Shanghai, China). DBDMH was obtained from Shanghai Aladdin Bio-Chem Technology Co., Ltd.
(Shanghai, China). PyBr3, BBr3, and AlCl3 were purchased from Beijing MREDA Technology Co., Ltd.
(Beijing, China). Succinimide was provided by Shanghai Macklin Biochemical Co., Ltd. (Shanghai,
China). Other chemical reagents and solvents were commercially available unless otherwise indicated.
3.2. Improved Prepared Process of LM49-API
As can be seen in Scheme 1, LM49-API was prepared starting from SM01 and SM02 by
Friedel–Crafts acylation, bromination, and demethylation reaction.
3.2.1. Preparation of Intermediate 2,4050-Trimethoxybenzophenone (LM49-01)
Anhydrous aluminum chloride (289 g, 2.17 mol) was added to 3.0 L CH2Cl2 and kept at a
temperature of 15 ◦C with stirring. SM01 (300 g, 2.17 mol) was slowly added into the mixture, which
was gradually changed to a light-yellow transparent solution. Then SM02 (409 g, 2.28 mol) was slowly
dropped into the system, which changed the color from light yellow to red-brown and allowed the
solution to warm to room temperature. The reaction process was monitored by TLC. After being stirred
for 1 h at room temperature, the mixture was slowly poured into 12 L ice water. The organic phase
was separated, and the water phase was extracted once with 3.0 L CH2Cl2. The combined organics
were washed with 3.0 L 5% NaOH water solution, dried over anhydrous sodium sulfate, and then
concentrated via rotary evaporation to obtain the light-yellow oily liquid, which was next dissolved
in 0.6 L CH2Cl2. 12 L n-hexane was added, stirred, and kept at 20 ◦C for 8 h. The precipitation was
filtered and dried at 35 ◦C to gain the white solid (461 g in 76.7% yield with 99.97% HPLC purity).
Mp 59–60 ◦C; 1H-NMR (400 MHz, DMSO-d6)
(dd, J = 7.4, 1.8 Hz, 1H), 7.17 (d, J = 1.8, 1H), 7.15 (dd, J = 15.6, 2.0 Hz, 1H), 7.07 (td, J = 7.5 Hz, 1H),
7.03 (d, J = 8.5 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H); 13C-NMR (100MHz, DMSO-d6)
194.6,
δ 7.51 (td, J = 1.8 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.26
δ
156.8, 153.8, 149.2, 131.8, 130.3, 129.3, 128.8, 125.8, 120.8, 112.2, 111.1, 110.9, 56.2, 55.9, 55.9; MS (ESI) m/z
(100%) 273 [M + H]+.
3.2.2. Preparation of Key Intermediate 5,20-Dibromo-2,4050-Trimethoxybenzophenone (LM49-02)
NBS (1137 g, 6.39 mol) was added into the solution of LM49-01 (435 g, 1.60 mol) in 2.2 L THF. The
mixture was stirred for 5 h at room temperature, then poured into 8 L ice water to quench the reaction.
The precipitation was filtered and separated to get the yellow-like solid, which was recrystallized at a
proportion of 1 g/10 mL of LM49-02/ethanol and dried at 50 ◦C to afford 460 g white granular solid
in 83.0% yield with 99.82% HPLC purity. Mp 133–134 ◦C; 1H-NMR (400 MHz, DMSO-d6)
J = 8.9, 2.5 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.21 (s, 1H), 7.13 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 3.74 (s, 3H),
δ 7.74 (dd,
3.66 (s, 3H), 3.30 (s, 3H); 13C-NMR (100MHz, DMSO-d6)
δ 192.8, 157.9, 151.8, 148.3, 136.5, 132.8, 132.5,
130.1, 116.6, 115.5, 113.7, 112.4, 111.6, 56.7, 56.6, 56.3; MS (ESI) m/z (100%) 429,431,433 [M + H]+.
3.2.3. Preparation of the Target Compound (LM49-API)
LM49-02 (450 g, 1.05 mol) was added to 2.25 L CH2Cl2, stirred to dissolve completely. Next,
BBr3 (786 g, 3.14 mol) was slowly dropped into the system at –15 ◦C. Then the mixture was allowed
to warm to room temperature. After stirring for 2 h, the reaction mixture was slowly poured into
9 L ice water to quench the reaction. The precipitation was filtered to obtain the yellow solid, which
was recrystallized with the mixed solvent of ethanol and water with the 1 g/4 mL/4 mL proportion of
LM49-API/ethanol/water and dried at 50 ◦C in a vacuum oven to afford 350 g light yellow crystal solid
in 88.3% yield with 99.98% HPLC purity. Mp 220–221 ◦C; 1H-NMR (400 MHz, DMSO-d6)
1H), 10.10 (brs, 1H), 9.61 (brs, 1H), 7.62 (dd, J = 8.8, 2.6 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.02 (s, 1H),
δ 10.83 (s,