Application of 6-aminotetrachlorophthalide_Kain Industrial Additive

Background and overview^[1][2]

The Chinese alias of 6-aminotetrachlorophthalide is 6-aminophthalide. 6-Aminophthalide can be used as an intermediate for pharmaceutical and chemical synthesis. If 6-aminophthalide is inhaled, please move the patient to fresh air; if the skin comes into contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical treatment if you feel uncomfortable; if the eyes come into contact, seek medical attention. Separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Apply^[1]

6-Aminophthalide can be used as an intermediate for pharmaceutical and chemical synthesis. Examples of its applications are as follows:

Step 1: Preparation of 6-bromoisobenzofuran-1(3H)-one (Int-1-c): Add compound (Int-1-b) (1.4g, 9.39mmol) in HBr aqueous solution ( Dissolve in 20 mL), add NaNO ₂ aqueous solution (648 mg, 9.39 mmol) dropwise in an ice bath, and stir at this temperature for 0.5 hours. The reaction solution was then poured into a mixed solution of CuBr (4.32g, 30mmol) and HBr aqueous solution (10mL), and stirred for 1 hour. The reaction solution was extracted with DCM, the organic phase was concentrated, and the residue was separated by silica gel column chromatography to obtain compound (Int-1-c) (870 mg, yield: 43.7%).

Step 2: Preparation of 3,6-dibromoisobenzofuran-1(3H)-one (Int-1): Dissolve compound (Int-1-c) (870mg, 4.1mmol) in CCl 4 (10mL), dilute Br ₂ (985mg, 6.1mmol) with CCl ₄, then add it dropwise to the reaction system, and finish the dripping After the reaction was completed for 5 hours, TLC monitored the reaction, the solvent was removed by rotary evaporation, and the residue was purified by thin layer preparative chromatography to obtain compound (Int-1) (620 mg, yield: 52.1%).

Preparation ^[2]

Method 1: Preparation of 6-aminoisobenzofuran-1(3H)-one (6-aminophthalide) (Int-1-b): 6-Nitroisobenzofuran-1(3H) )-ketone (Int-1-a) (1.79 g, 10 mmol) was dissolved in MeOH (30 mL), Pd/C (179 mg) was added, and stirred under hydrogen atmosphere overnight. The reaction solution was then suction filtered and concentrated to obtain compound 6-aminophthalide (Int-1-b) (1.4 g, yield: 94.0%).

Method 2: The preparation of 6-aminophthalide is as follows:

Step A: Preparation of 6-nitroisobenzofuran-1(3H)-one. To a 2000 mL 3-neck round bottom flask was added a solution of isobenzofuran-1(3H)-one (130 g, 970.15 mmol, 1.00 equiv) in sulfuric acid (200 mL). Then a solution of potassium nitrate (196g, 1.94mol, 1.39 equivalent) in sulfuric acid (600mL) was added dropwise with stirring at 0°C. The reaction mixture was stirred at room temperature overnight. The solid was collected by filtration and washed with 5 × 800 mL H2O. 136 g (crude product) of 6-nitroisobenzofuran-1(3H)-one was obtained as a white solid.

Step B: Preparation of 6-aminoisobenzofuran-1(3H)-one (6-aminophthalide). To a 2000 mL 3-neck round bottom flask, add a solution of 6-nitroisobenzofuran-1(3H)-one (prepared as described in the above step, 136 g, 759.78 mmol, 1.00 equiv) in water (50 mL), Fe (126.4g), ethyl acetate (500mL), acetic acid (180mL). The reaction mixture was stirred in an oil bath at 60°C for 2 hours.

Add 500 mL of sodium bicarbonate to the resulting mixture. The resulting solution was extracted with 5×500 mL of ethyl acetate. The combined organic layers were washed with 500 mL of brine, dried (Na2SO4), and concentrated in vacuo. The title compound was obtained as a yellow solid. LC-MS (ES, m/z) 150 [M+H]+

Main reference materials

[1] WO2018149284. Kinase inhibitors and preparation methods and uses thereof

[2] WO2011159854.CYCLOHEXYL-AZETIDINYL ANTAGONISTS OF CCR2