Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline

A technology of trifluoromethylbenzoic acid and trifluoromethyl, applied in the field of preparation of 3--5-aniline, can solve the problems of low yield and high cost of raw materials

Active Publication Date: 2015-05-06
ASYMCHEM LAB TIANJIN +4
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Problems solved by technology

[0014] The present invention aims to provide a kind of preparation method of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, to solve the problem of preparing 3-(4-methyl)aniline in the prior art. Base-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline has the defects of high raw material cost and low yield

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  • Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline
  • Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline
  • Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline

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preparation example Construction

[0046]As described in the background technology section, the existing method for preparing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline has the defects of high raw material cost and low yield . In order to solve this problem, the present inventor provides a kind of preparation method of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, which comprises the following steps: S1 , carry out coupling reaction between compound A and 4-methyl-1H-imidazole to generate a coupled product; S2, carry out hydrazinolysis reaction on the coupled product to generate a hydrazinolysis product; and S3, subject the hydrazinolysis product to diazonium in turn Chemical reaction, Curtius rearrangement reaction, generate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline; Wherein, compound A is selected from 3-halo-5-trifluoro Toluic acid, salt derivatives of 3-halo-5-trifluoromethylbenzoic acid or ester derivatives of 3-halo-5-trifluoromethylbenzoic acid.

[0047] The abo...

Embodiment 1

[0078] Coupling reaction: Add methyl 3-bromo-5-trifluoromethylbenzoate (compound 2, 200g, 0.707mol), 4-methyl-1H-imidazole (116g, 1.41mol), trans-N , N'-dimethylcyclohexanediamine (20g, 0.14mol), DMF (8vol / g, relative to compound 2), anhydrous potassium phosphate (300g, 1.41mol) and 4A molecular sieve (0.1g / g), A mixed system is formed; the mixed system is replaced with nitrogen to oxygen content ≤ 500ppm, and finally cuprous iodide (26.9g, 0.14mol) is added to form a system to be reacted; Track the reaction until compound 2 disappears (44 hours) to obtain the product system; then the system is cooled to room temperature, quenched in 2M hydrochloric acid to obtain the solution to be purified; ethyl acetate is added to the solution to be purified, and the organic phase is obtained by extraction and separation , the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined; the organic phase was concentrated to remove the ethyl acetate solvent to...

Embodiment 2

[0083] Coupling reaction: Add 3-bromo-5-trifluoromethylbenzoate sodium (compound 2, 29g, 0.1mol), 4-methyl-1H-imidazole (16.4g, 0.2mol), trans-N ,N'-Dimethylcyclohexanediamine (2.8g, 0.02mol), DMF (8vol. / g), anhydrous potassium phosphate (42g, 0.2mol) and 4A molecular sieve (0.1g / g) to form a mixed system ; The mixed system is replaced with nitrogen to oxygen content ≤ 500ppm, and finally copper iodide (3.8g, 0.02mol) is added to form a system to be reacted; the system to be reacted; the temperature is raised to 115 ° C, and the reaction is stirred for 60 hours, TLC tracking showed that compound 2 disappeared to obtain the product system; the product system was cooled to 30-35° C., and bromoethane (30 g, 0.275 mol) was added dropwise thereto, and the coupling carboxylic acid generated in situ was completely ethylated by TLC tracking. The system was lowered to room temperature, quenched with 2M hydrochloric acid, added ethyl acetate, extracted and separated to obtain the organi...

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Abstract

The invention provides a preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline. The method includes: S1. subjecting a compound A and 4-methyl-1H-imidazole to coupling reaction to generate a coupling product; S2. carrying out hydrazinolysis reaction on the coupling product to generate a hydrazinolysis product; and S3. subjecting the hydrazinolysis product to diazotization and Curtius rearrangement reaction in order to generate 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline. Specifically, the compound A is 3-halogen-5-trifluoromethylbenzoic acid, a salt derivative of 3-halogen-5-trifluoromethylbenzoic acid or an ester derivative of 3-halogen-5-trifluoromethylbenzoic acid. The method for preparation of 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline provided by the invention has the characteristics of short synthesis route, low cost of raw materials, mild reaction conditions and high yield, thus being applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. Background technique [0002] Nilotinib is a potent and precise second-generation tyrosine kinase inhibitor. The indications are adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) in chronic phase or accelerated phase who are resistant or intolerant to previous treatment (including imatinib). [0003] [0004] There are many patents reporting different synthetic methods of nilotinib. Among them, 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline is a very important key intermediate, and the vast majority of existing patents and documents use it as Raw material synthesized nilotinib. The chemical formula of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline is as follows: [0005] [0006] At present, the preparation method of 3-(4-methyl-1H-i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/61
CPCC07D233/61
Inventor 洪浩李九远黄高超李常峰
Owner ASYMCHEM LAB TIANJIN
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