Preparation method of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amino]benzoic acid, related intermediate and application thereof

Abstract

The invention provides a preparation method of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amino]benzoic acid. The preparation method comprises the following steps of: carrying out a guanidine-forming reaction on 3-amino-4-methyl toluic acid and cyanamide under the acidic condition of hydrochloric acid to generate 3-[(aminoiminomethyl)amino]-4-methyl-benzoic acid-hydrochloride, and then carrying out a cyclization reaction on the 3-amino-4-methyl toluic acid and cyanamide and 3-(dimethylamino)-1-(3-pyridyl)-2-propylene-1-one to generate the 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amino]benzoic acid, wherein a structural formula of the 3-[(aminoiminomethyl)amino]-4-methyl-benzoic acid-hydrochloride is shown as the description. The method has short route, simple operation, safe and environmentally-friendly process, repeatability, low cost, high yield, high stability and safety of a guanidine hydrochloride intermediate, suitability for large-scale industrial production and higher economic benefit and social benefit.

Description

technical field The present invention relates to the technical field of nilotinib intermediates, more specifically, to a preparation method of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid and related intermediates body, as well as the preparation and application of the intermediate. Background technique 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl] amino] benzoic acid is an important intermediate of anticancer drug nilotinib, and its structure is as shown in formula (I): CAS number: 641569-94-0, English name: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid. Its synthesis process was first reported in the patent US 7169791 (applicant: NOVARTIS AG, publication date: January 30, 2007), and the specific route is as follows: Mentioned in the embodiment 1a-1c of the patent US 7169791 (Chinese family: CN 1675195): This route uses ethyl 3-amino-4 methylbenzoate as a raw material, reacts with cyanamide to prepare its guanidine nitrate compound 2 ...

AI Technical Summary

Problems solved by technology

The problem that exists is: the guanidine nitrate salt of ester, stability and safety are lower; The nitrate material consumption of the intermediate guanidine of preparation ester is more (mainly refers to the mononitrile ammonia consumption, generally needs 4-5 equivalent); And The purity of the product is poor, and the post-treatment needs to be washed with ether or isopropyl ether. The operation is more cumbersome and the yield is lower.

Similarly, the cyclization and hydrolysis process of the final product produced by the guanidinium nitrate salt of the ester has problems such as unstable yield (the experimenter repeats this route, about 45-55%) and incomplete reaction.

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