Background and overview[1]
3-Bromo-2-methylbenzyl alcohol is a pharmaceutical intermediate that can be prepared by esterifying 3-bromo-2-methylbenzoic acid and then reducing it. There are reports in the literature that 3-bromo-2-methylbenzyl alcohol can be used to prepare a fused ring compound, which can be used as a PD-1/PD-L1 inhibitor. It has high activity, high bioavailability, drug stability, and can be taken orally. Advantages of drug administration.
Preparation[1]
Step 1: Synthesis of Compound I-1B
Dissolve compound I-1A (10.7g, 50mmol) in methanol (100ml), then add 2ml of concentrated sulfuric acid, and react the resulting reaction solution at 60 degrees Celsius overnight. After TLC showed that the reaction was completed, cool to room temperature, spin off the methanol, and add saturated ammonium chloride solution (250 ml). Extract with ethyl acetate (150 mL Thermoplastic elastomer petroleum ether/ethyl acetate = 10/1 (volume ratio V/V)) to obtain compound I-1B (9.9 g, light yellow liquid), yield: 87%. MS m/z(ESI):229[M+1].
Step 2: Synthesis of Compound I-1C
Dissolve compound I-1B (4.56g, 20mmol) in anhydrous THF solution (100ml). After cooling to 0 degrees Celsius, add LAH (0.8g, 20mmol) in batches to keep the internal temperature of the reaction solution less than 5 degrees Celsius. , after the addition is completed, slowly raise the temperature to room temperature and react for 2 hours. After TLC shows that the reaction is completed, re-cool to 0 degrees Celsius, add 0.8ml water, 0.8ml NaOH with a concentration of 15% and 2.4ml water in sequence, and stir for 1 hour after the addition. , filtered, and the filtrate obtained was spun to dryness to obtain compound I-1C, which is 3-bromo-2-methylbenzyl alcohol (3.7g, yellow solid), yield: 92.4%.
Main reference materials
[1] [Chinese invention] CN201910087327.X A fused ring compound and its application
