Preparation of 5-bromoaminobenzoic acid methyl ester and its application in organic synthesis_Kain Industrial Additive

Background and Overview

5-Methyl bromoaminobenzoate is an ester compound, mainly used as an organic intermediate in organic synthesis.

Preparation^[1]

Method 1

Add 302mg (2mmol) methyl anthranilate and 143mg (1.2mmol) potassium bromide into a 50ml three-neck flask, and then add AcOH: H₂O=9:1 Transfer 10ml of solvent to a constant temperature magnetic stirring water bath, control the temperature to 30°C, stir and react for 1 hour, and slowly add 1.8g (1.8mmol) ZnAl-BrO₃ in batches within 15 minutes before the reaction. –LDHs. After the reaction is completed, extract the reaction solution with dichloromethane, combine the organic phases, add two spoonfuls of column chromatography silica gel (200-300 mesh) to the dichloromethane phase, and distill off the dichloromethane under reduced pressure. 359 mg of pure product was isolated by chromatography (petroleum ether: ethyl acetate = 10:1 as eluent). The material was an off-white solid and the yield was 78%.

Characterization data: mp 73-74℃. ¹H NMR (500MHz, CDCl3) δ: 7.98 (d, J = 2Hz, 1H), 7.34 (d, J = 9Hz, 1H), 6.58 (d, J＝9Hz,1H),5.77(s,2H),3.89(s,3H).

¹³C NMR(125MHz, CDCl3)δ:167.4,149.3,136.6,133.3,118.3,111.9,107.2,51.7.

HRMS(ESI,m/z):Calculated for C8H8BrNO2(M+H)⁺229.9811,found 229.9819.

Method 2: Dissolve 2-amino-5-bromobenzoic acid (80g, 0.37mmol) in methanol (600mL), then H₂SO₄ (50mL ) solution was added slowly. The reaction mixture was refluxed for 72 h and then concentrated. NaOH solution was added to adjust the pH to 10‑11. The mixture was extracted with EtOAc (3×500mL). The combined organic layers were dried over MgSO₄ and concentrated to provide the desired compound as a colorless oil (65g, yield: 76%)

Apply^[3]

Methyl 5-bromoaminobenzoate can be used in the preparation of cetilixstat. Cetilistat (2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one, cetilistat) is a long-acting and potent drug developed by Alizyme Specific gastrointestinal lipase inhibitors form covalent bonds with the active serine sites of gastric lipase and pancreatic lipase in the stomach and small intestine to inactivate the enzymes, thereby achieving the therapeutic effect of reducing caloric intake and controlling weight. CN201410556475.9 reports a preparation method of cetilistat, which uses 2-amino-5-bromobenzoic acid methyl ester as the starting material, has low cost, convenient preparation, and is easy for industrial production. The steps are as follows:

1: Preparation of methyl 2-(hexadecyloxycarbonylamino)-5-bromobenzoate

Add 4.9g triphosgene into 50mL dichloromethane, cool to 0°C, and add dropwise 2-amino-5-bromobenzoic acid methyl ester (5g) and triethylamine (13.8mL) in dichloromethane ( 20mL) solution, after the dropwise addition, keep it at 0°C for 15min, then rise to room temperature and stir for 2h. Add 5.26g of cetyl alcohol to the above reaction solution and react at room temperature for 2 hours. After the reaction is completed, filter, the filtrate is concentrated in a vacuum and spin-dried, the residue is beaten and washed with anhydrous methanol, filtered, and the filter cake is dried to constant weight. 9.1 g of white powder solid was obtained, which was 2-(hexadecyloxycarbonylamino)-5-bromobenzoic acid methyl ester; yield: 85%.

2: Preparation of methyl 2-(hexadecyloxycarbonylamino)-5-methylbenzoate

Under nitrogen protection, dissolve 10g of 2-(hexadecyloxycarbonylamino)-5-bromobenzoic acid methyl ester in 1,4-dioxane (50mL) and water (5mL), add 11g of free Aqueous potassium carbonate, 1.44g methylboronic acid, 0.731g Pd(dppf)2Cl2, the mixture was reacted at 105°C for 3 hours. After the reaction is completed, cool down, filter, spin the filtrate to dryness, wash the residue with anhydrous methanol, filter, and dry the filter cake to obtain 6.5g of gray solid, which is 2-(hexadecyloxycarbonylamino)-5-methylbenzoic acid. Methyl ester, yield 75%.

3: Preparation of 2-(hexadecyloxycarbonylamino)-5-methylbenzoic acid

Add 7g of methyl 2-(hexadecyloxycarbonylamino)-5-methylbenzoate into a mixture of 35mL of tetrahydrofuran and 7mL of water, add 20.1g of lithium hydroxide, and react at 60°C for 3 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is added to 70 mL of ice water, adjusted to pH 7 with 6M hydrochloric acid, filtered, and the filter cake is dried to constant weight to obtain 6.2 g of gray solid, which is 2-(hexadecyloxycarbonylamino)-5 -Toluic acid, yield 92%.

4: Preparation of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (cetilistat)

Place 66g of 2-(hexadecyloxycarbonyl(Amino)-5-methylbenzoic acid was suspended in 330 mL of pyridine. Under an ice bath, 45 mL of ethyl chloroformate was slowly added dropwise. After the dropwise addition was completed, it was naturally raised to room temperature for 3 h. After the reaction is completed, the reaction solution is poured into 700 mL of ice water, filtered, and the filter cake is dried to a constant weight to obtain 56 g of gray solid, which is 2-hexadecyloxy-6-methyl-4H-3,1-benzo. Oxazin-4-one (cetilista), yield 85%.