Background and overview[1]
2-Methyl-4-(2-methylbenzamido)benzoic acid is an important intermediate in the preparation of tolvaptan, which is a product developed by Otsuka Company of Japan. Non-peptide selective V2 receptor antagonists can reduce body fluid load without affecting electrolyte balance and renal function, and are suitable for the treatment of hyponatremia and other diseases. The U.S. FDA approved tolvaptan tablets in 2009, with the trade name samsca, for the treatment of patients with heart failure and other diseases.
Preparation[1]
Step 1: Preparation of 2-methyl-4-aminobenzaldehyde
Under ice bath, drop phosphorus oxychloride (34.3g) into N,N-dimethylformamide (60ml), keep stirring at 0~5℃ for 1h, then add 3-methylaniline (20g) , the temperature was raised to 60°C and the reaction was stirred for 6 hours. Cool the reaction solution to room temperature, add ice water (120ml), adjust pH to 8 with 2M NaOH, extract twice with ethyl acetate (120ml each time), combine the ethyl acetate layer and wash twice with water (60ml each time), anhydrous sulfuric acid Dry over sodium, suction filter, and evaporate the ethyl acetate to dryness under reduced pressure to obtain 2-methyl-4-aminobenzaldehyde. After recrystallization and purification from acetone, 20.8g of light yellow solid was obtained, with a yield of 82.5% and a purity of 97.2% (HPLC area normalization method), m.p: 82~84°C, HRMS (ESI+): m/z=136.0665.
Step 2: Preparation of 2-methyl-4-aminobenzene cyanide
Add 2-methyl-4-aminobenzaldehyde (20g) to formic acid (100ml), then add hydroxylamine hydrochloride (15.5g) and sodium formate (23g), and heat to 100°C for 3 hours. Formic acid was evaporated under reduced pressure, cooled to room temperature, water (200ml) was added, stirred for 1 hour, and filtered with suction to obtain 17.8g of yellow 2-methyl-4-aminobenzene cyanide solid, yield 91.2%, purity 98.5%, m.p: 74 ~76℃, HRMS(ESI+): m/z=133.0691.
Step 3: Preparation of 2-methyl-4-aminobenzoic acid
Add 2-methyl-4-aminobenzene cyanide (10g) to ethylene glycol (50ml) and water (50ml), then add sodium hydroxide (15g), and heat the mixture to 100°C for 6 hours. Cool to room temperature, add concentrated hydrochloric acid dropwise to adjust the pH of the system to 4~5, stir for 2 hours, and filter with suction to obtain 11.0g of 2-methyl-4-aminobenzoic acid solid, yield 95.6%, purity 99.4%, m.p: 160~164℃, HRMS(ESI+): m/z=152.0622.
Step 4: Preparation of 2-methyl-4-(2-methylbenzamido)benzoic acid
Dissolve 2-methyl-4-aminobenzoic acid (10g) in acetone (150ml), then add triethylamine (8.7g), cool the reaction solution to 0~5°C, and start adding 2-methyl Benzyl benzoyl chloride (12.2g), control the temperature during dropwise addition to 0~10°C. After the dropwise addition is completed, raise the temperature to 30°C and react for 10h. After the reaction is completed, add ice water (150 ml), stir for 0.5 h, and filter with suction to obtain 2-methyl-4-N-(2-methylbenzoyl)benzoic acid. Purify with a mixed solvent of ethyl acetate and ethanol to obtain 16.6g of white solid 2-methyl-4-(2-methylbenzamido)benzoic acid, yield 93.5%, purity 99.7%, m.p: 230~232 ℃, HRMS (ESI+): m/z=270.1031.
References
[1] CN201711349574.X Preparation method of tolvaptan intermediate 2-methyl-4-N-(2-methylbenzoyl)benzoic acid
