Preparation method of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride_Kain Industrial Additive

Background and overview^[1]

4-(4-Methyl-1-piperazinylmethyl)benzoic acid dihydrochloride is a key intermediate for the preparation of imatinib mesylate. Imatinib mesilate, chemical name is 4-(4-methylpiperazinyl-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl) Pyrimidine-2-amino]-benzamide methanesulfonate. Imatinib mesylate is a small molecule tyrosine kinase (TK) inhibitor. Its mechanism of action is to target the bcr/abl receptor subtype of tyrosine kinase and selectively bind to bcr/abl protein tyrosine kinase catalysis. In the nucleotide binding cavity of the region, it competitively prevents tyrosine kinase from binding to ATP. It can recognize the inactivated conformation of the activation loop of tyrosine kinase and specifically bind to it to prevent autophosphorylation and phosphorylation of tyrosine kinase substrates, reduce tyrosine kinase activity, and inhibit or control tumor occurrence. It is clinically used to treat chronic myeloid leukemia (CML). It was developed by the Swiss company Novartis and was approved by the FDA in 2001.

Preparation^[2]

Method 1: A preparation method of 4-(4-methyl-1-piperazinylmethyl)benzoic acid dihydrochloride, which includes the following steps:

(1) Add 4-methylpiperazine to n-butanol, then add p-chloromethylbenzoic acid at 20-40°C, and then perform an insulating reaction at 30-40°C. Control p-chloromethylbenzoic acid When the methylbenzoic acid content is less than 1%, the reaction is completed. After the reaction, the excess 4-methylpiperazine and n-butanol are evaporated from the reaction solution by concentrating under reduced pressure. Water 1 to 3 times the weight of p-chloromethylbenzoic acid is added to the residue. , then neutralize with concentrated hydrochloric acid to pH=1~2, then add methanol 8~12 times the weight of p-chloromethylbenzoic acid, then raise the temperature to 50~65°C to dissolve, then cool to 0~10°C to crystallize, and filter to obtain Solid crystallization, the solid crystallization is washed with methanol 1 to 2 times the weight of p-chloromethylbenzoic acid, and then dried at 50 to 60°C to obtain a crude product;

(2) Add the crude product obtained above into water with 2 to 5 times the weight of p-chloromethylbenzoic acid, raise the temperature to 50 to 60°C, stir and dissolve, and then add methanol, ethanol or methanol dropwise within 2 to 5 hours. The dropping amount of isopropyl alcohol, methanol, ethanol or isopropyl alcohol is 10 to 15 times the weight of p-chloromethylbenzoic acid. After dripping, slowly cool to 0 to 10°C to precipitate a white solid. Filter to obtain a white solid. Dry at 50-60°C to obtain the finished product 4-(4-methyl-1-piperazinylmethyl)benzoic acid dihydrochloride.

Method 2: Dissolve p-cyanobenzyl chloride (1g, 6.6mmol) in a mixed solvent of ethanol and water (10mL, ethanol:water=2:1 in the mixed solvent), add methylpiperazine (1.2eq , 0.792g, 7.92mmol), heat the reaction at 70°C, the reaction time is 1-2 hours, cool to room temperature, recover most of the ethanol, and obtain 4-(4-methyl-1-piperazinyl) benzonitrile, Add sodium hydroxide (6eq, 1.584g, 39.6mmol), heat the reaction at 70°C, wait until the reaction is complete, cool to room temperature, slowly add dilute hydrochloric acid dropwise in an ice bath until pH=1, add sodium chloride until saturated , cool and precipitate a solid, filter and dry to obtain 4-(4-methylpiperazin-1-ylmethyl)benzoic acid hydrochloride (2.0g).

Main reference materials

[1] CN201510253597.5 Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl)benzoic acid hydrochloride

[2] CN201710135495.2 Preparation method of 4?(4?methyl?1?piperazinylmethyl)benzoic acid dihydrochloride