Preparation of 3-bromo-5-nitrobenzamide_Kain Industrial Additive

Background and overview^[1][2]

3-Bromo-5-nitrobenzamide is a poly(ADP-ribose) polymerase inhibitor. As an anti-tumor agent, it is currently in the clinical research stage and has good clinical prospects.

3-Bromo-5-nitrobenzamide

Preparation^[2]

Method 1:

Step 1: Preparation of 3-nitrile-5-nitroaniline.

Into a 500ml three-necked flask, add 21.6g (0.1mol) 3-bromo-5-nitroaniline, 10g (0.12mol) cuprous cyanide, 200ml DMF, stir, and heat to React at 60°C for 5 hours. TLC spot detection shows that the reaction is complete. Cool to room temperature, distill, and remove the solvent to obtain the residue. Extract with ethyl acetate (20 ml × 3), distill under reduced pressure, and recrystallize from ethanol to obtain a reddish solid 14.5. g, yield: 70.2%.

MS(+1): 164. 1HNMR: d(ppm, CDCl3), 8.19(s, 1H), 7.64-7.65(d, 1H), 6.92-6.93(d, 1H), 4.237-4.24(br ,2H).

Step 2: Preparation of 3-bromo-5-nitrobenzonitrile (compound III)

Add 32.6g of Intermediate II (0.2mol), 540mL of distilled water, and 50mL of concentrated hydrochloric acid into a 2L three-necked flask, stir mechanically, and cool down to 0-5°C in an ice bath. The reaction solution will become a yellow slurry. Dissolve 20.7g sodium nitrite (0.3mol) in 230mL of water, slowly add it dropwise into the above reaction system, some solids will be dissolved, control the temperature in the system to 0-5°C, continue stirring to complete the addition, and control the temperature for 3 hours. Suction filtration was performed to obtain a yellow solid and filtrate, and the filtrate was transferred to a 3L three-necked flask. Dissolve 66g potassium bromide (0.4mol) in 148mL water, slowly add it dropwise into the reaction system, and a large number of bubbles will be generated. After adding, continue stirring for 2 hours, and filter with suction to obtain an orange-red filter cake, which is blast dried at 60°C to a constant weight. , 47.6g of orange-red solid was obtained, with a yield of 86.8%.

MS(+1): 275. 1HNMR: d (ppm, CDCl3), 8.21 (s, 1H), 8.02-8.03 (d, 1H), 7.67-7.68 (d, 1H).

Step 3: Preparation of 3-bromo-5-nitrobenzamide

In a 250ml three-necked flask, add 27.5g (0.1mmol) compound III and 200ml concentrated hydrochloric acid, stir, raise the temperature to 80°C and react for 5 hours. TLC spotting test shows that the reaction is complete. Cool to room temperature, separate out the solid, and filter with suction. , vacuum drying to obtain 26.3g of white solid 3-bromo-5-nitrobenzamide, yield: 90.1%.

MS(+1):293. HNMR: d (ppm, CDCl3), 8.65 (s, 1H), 8.11-8.12 (d, 1H), 8.08-8.09 (d, 1H), 6.12-6.13 (s, 2H).

Method 2:

Put 3.7g 3-bromo-5-nitrobenzoic acid methyl ester and 30mL methanol into the reaction bottle, stir at 35°C, vent ammonia gas, and monitor the reaction progress with TLC. The volume ratio of the developing agent is ethyl acetate:petroleum ether = 1:1. After the reaction was completed, the reaction solution was evaporated to dryness to obtain 3.3g of crude yellow solid product. The crude product was recrystallized with 19.8 mL of ethanol, filtered with suction to obtain yellow crystals, and dried under vacuum to obtain 3.0 g of 3-bromo-5-nitrobenzamide, with HPLC purity of 99.75% and yield of 85.2%.

Main reference materials

[1] Meng Fande, & Li Mingxia. (1999). Synthesis of N-(4-ethoxy-3,5-diethylamino)phenyl-p-nitrobenzamide. West China Journal of Pharmacy, 14( 6), 362-363.

[2] Qin Weiyan, Liu Bo, You Jun, Ma Jing, Li Xiang, & Lu Chengcheng. (2012). “One-pot method” synthesis of 2-amino-n,3-dimethyl-5-halogenated benzyl Amides. Organic Chemistry, 32(5), 896-899.

[3] Xu Liangzhong, Han Zongling, Shi Ying, Liu Yu, Fu Haifeng, & Gao Shukun et al. (2013). Synthesis and insecticidal activity testing of fluorinated o-carboxamidobenzamides. Pesticides, 52( 1), 15-18.