2-iodo-5-(methoxycarbonyl)benzoic acid synthesis

Yield:1048025-64-4 77%

Reaction Conditions:

Stage #1: 4-amino-benzene-1,3-dicarboxylic acid,1-methyl esterwith hydrogenchloride;sodium nitrite in water;acetone; for 2 h;
Stage #2: with potassium iodide in water;acetone at 0; for 0.5 h;

Steps:

2-Iodo-N-isopropyl-5-methoxycarbonylbenzamide (21)

A solution of sodium nitrite (75 mg, 1.08 mmol) in water (0.54 mL) was added dropwise to a solution of 2-amino-5-methoxycarbonylbenzoic acid [4] (106 mg, 0.55 mmol) in a 7:3:1 mixture of water (1.9 mL), acetone (0.8 mL), and concentrated HCl (0.26 mL). After stirring for 2 h, potassium iodide (179 mg, 1.08 mmol) was added to the mixture. The resulting mixture was stirred at 0 C for 0.5 h and then allowed to warm to room temperature. The mixture was extracted with CHCl3. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give methyl 2-iodo-5-methoxycarbonylbenzoic acid[3] (130 mg, 77%) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 8.64 (1H, d, J = 1.8 Hz), 8.17 (1H, d, J = 8.2 Hz),7.83 (1H, dd, J = 8.2, 1.8 Hz), 3.96 (3H, s). A solution of 2-iodo-5-methoxycarbonylbenzoic acid (118 mg, 0.39 mmol) in thionyl chloride (1.5 mL) was heated at reflux with stirring for 2 h. The resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH2Cl2 (1.3 mL). To the mixture were added isopropylamine (28 mg, 0.47 mmol) and triethylamine (121 mg, 1.2 mmol) at 0 °C under a nitrogen atmosphere. After stirring at room temperature for 1 h, the resulting solution was diluted with EtOAc. The mixture was washed with 10% HCl, saturated aqueous NaHCO3, water,and brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl3 to give 21 (65 mg, 48% in 2 steps) as colorless prisms.

References:

Yakura, Takayuki;Fujiwara, Tomoya;Yamada, Akihiro;Nambu, Hisanori [Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 971 - 978] Location in patent:supporting information