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Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

A technology of trifluoromethylaniline and trifluoromethyl, which is applied in the field of preparation of nilotinib intermediate 3--5-aniline, can solve the problems of low reaction yield, large environmental pollution, and unsuitability for industrial production

Inactive Publication Date: 2016-09-21
ZHEJIANG ESIGMA BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this synthetic method has problems such as high production cost, low reaction yield, and large environmental pollution, and is not suitable for industrialized production.

Method used

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  • Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] In the there-necked flask, add 24g (0.1mol) 3-bromo-5-trifluoromethylaniline, 8.2g (0.1mol) 4-methylimidazole, 65.2g (0.2mol) Cs 2 CO 3 , 1.9g (0.01mol) CuI, 2.2g (0.01mol) D-glucosamine hydrochloride, then add 50mL DMSO and 50mL water, stir to dissolve, control the reaction temperature at 100°C, and continue the reaction for 10 hours. Add 100mL ethyl acetate after completion of the reaction, get the supernatant after centrifugation, concentrate and dry to obtain 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, the HPLC purity is 98.53%, the yield is 95.25%.

Embodiment 2

[0022] In the reaction vessel, add 24g (0.1mol) 3-bromo-5-trifluoromethylaniline, 8.2g (0.1mol) 4-methylimidazole, 58.7g (0.18mol) Cs 2 CO 3 , 0.95g (0.005mol) CuI, 1.1g (0.005mol) D-glucosamine hydrochloride, then add 60mL DMSO and 80mL water, stir to dissolve it, control the reaction temperature to 90°C, and continue to react for 12 hours. After completion, 120 mL of ethyl acetate was added, and the supernatant was taken after centrifugation, concentrated and dried to obtain 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. The HPLC purity was 98.66%, and the yield was 96.18%.

Embodiment 3

[0024] In the reaction vessel, add 24g (0.1mol) 3-bromo-5-trifluoromethylaniline, 8.2g (0.1mol) 4-methylimidazole, 71.7g (0.22mol) Cs 2 CO 3 , 3.8g (0.02mol) CuI, 4.4g (0.02mol) D-glucosamine hydrochloride, then add 80mL DMSO and 60mL water, stir to make it dissolve, control the reaction temperature to be 110°C, and continue to react for 8 hours. After completion, add 160 mL of ethyl acetate, take the supernatant after centrifugation, concentrate and dry to obtain 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. The HPLC purity was 98.09%, and the yield was 95.77%.

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Abstract

The invention provides a preparation method of a nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. The preparation method comprises the following steps of adding 3-bromo-5-(trifluoromethyl)aniline, 4-methylimidazole, D-glucosamine hydrochloride, CuI, Cs2CO3, DMSO and water into a reaction vessel in sequence, and reacting for 8 to 12 hours at 90 to 110 DEG C; adding ethyl acetate into reaction liquid, taking a supernatant after centrifugal separation, and obtaining the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline after concentration and drying. The purity of a product prepared by the invention can reach 98 percent or above, the yield can reach 95 percent or above, and the preparation method provided by the invention has the advantages of being low in production cost, high in reaction yield, low in environmental pollution and the like, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. Background technique [0002] Nilotinib is a new type of ATP competitive inhibitor, which is based on aminopyrimidine and has high affinity. Nilotinib can combine with ABL tyrosine kinase to promote the folding of the P-ring, thereby covering the ATP binding site, hindering the binding of the substrate, and cannot successfully complete the phosphorylation of ATP, thereby inhibiting the activity of the enzyme. Generates an inactive conformation of the BCR / ABL protein. Nilotinib hydrochloride hydrate can be used to treat chronic myelogenous leukemia that has been ineffective for imatinib mesylate, and selectively inhibit Philadelphia chromosome-positive chronic myelogenous leukemia caused by tyrosinase mutations. [0003] 3-(4-methyl-1H-imidazol-1-yl)-5...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/61
CPCC07D233/61
Inventor 闻鸣徐天华吴中华何奇雷
Owner ZHEJIANG ESIGMA BIOTECH CO LTD
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