Preparation method of nilotinib intermediate

Abstract

The invention relates to a preparation method of a nilotinib intermediate, namely, 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)aniline (I). The preparation method comprises the steps that 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)benzoic acid (VII) is subjected to Curtius rearrangement to generate a by-product compound (III) and then subjected to further reacting to be converted into 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)aniline (I). The preparation method has the advantages of being high in utilization rate of the raw materials and suitable for industrialized operation. Please see the formula in the description.

Description

technical field

[0001] The invention relates to the technical field of pharmaceutical intermediates, in particular to the nilotinib intermediate 3-(trifluoromethyl)-5-(4-methyl-1 H - a process for the preparation of imidazol-1-yl)aniline. Background technique

[0002] Nilotinib, the chemical name is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl]-3-[[ 4-(3-pyridyl)-2-pyrimidinyl]amino]benzamide is a highly selective oral tyrosine kinase inhibitor developed by Swiss Novartis Pharmaceuticals, and its monohydrochloride monohydrate was released in 2007 In October, it was approved by the US FDA for marketing, and it is clinically used for the treatment of chronic myelogenous leukemia that is ineffective for imatinib mesylate. Nilotinib can selectively inhibit Philadelphia chromosome-positive chronic myelogenous leukemia caused by mutations in tyrosinase and its coding gene through targeting. It has good tolerance, strong selectivity and significant curative e...

Examples

preparation example Construction

[0026] The preparation method of the compound (I) provided by the present invention comprises: further reacting and converting the by-product compound (III) formed by the Curtis rearrangement of the compound (VII) into the compound (I).

[0027] The present invention has no special requirements on the source of the main raw material compound (VII), which can be commercially available or prepared according to the prior art.

[0028] In the preparation method of the compound (I) provided by the invention, the compound (III) as a reaction by-product can be isolated separately, and converted into the target compound (I) through further reaction; the compound (III) can also be separated without isolation, And together with compound (II) under the same reaction conditions, it can be converted into compound (I) at the same time.

[0029] But preferably compound (III) and compound (II) are not separated, but are converted into compound (I) simultaneously under the same reaction condit...

Embodiment 1

[0053] Compound (VII) (10 g), tert-butanol (300 mL), triethylamine (7.9 g) and diphenylphosphoryl azide (11.2 g) were added to a 500 mL reaction flask. Stirring was started, the mixture was heated to reflux and maintained at reflux for 16 hours, then cooled to room temperature, the solvent was removed by evaporation under reduced pressure, the residue was treated with water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The extracts were combined, washed with brine (150 mL), dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude product (12.1 g).

Embodiment 2

[0055] The crude product (12.1 g) obtained in Example 1 was purified by chromatography (silica gel, eluting with ethyl acetate containing 2% ethanol) to obtain two components, which were recrystallized from ether-hexane respectively to obtain a solid compound ( II) (5.25g) and solid compound (III) (3.76g).

technical field

[0001] The invention relates to the technical field of pharmaceutical intermediates, in particular to the nilotinib intermediate 3-(trifluoromethyl)-5-(4-methyl-1 H - a process for the preparation of imidazol-1-yl)aniline. Background technique

[0002] Nilotinib, the chemical name is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl]-3-[[ 4-(3-pyridyl)-2-pyrimidinyl]amino]benzamide is a highly selective oral tyrosine kinase inhibitor developed by Swiss Novartis Pharmaceuticals, and its monohydrochloride monohydrate was released in 2007 In October, it was approved by the US FDA for marketing, and it is clinically used for the treatment of chronic myelogenous leukemia that is ineffective for imatinib mesylate. Nilotinib can selectively inhibit Philadelphia chromosome-positive chronic myelogenous leukemia caused by mutations in tyrosinase and its coding gene through targeting. It has good tolerance, strong selectivity and significant curative e...

Examples

preparation example Construction

[0026] The preparation method of the compound (I) provided by the present invention comprises: further reacting and converting the by-product compound (III) formed by the Curtis rearrangement of the compound (VII) into the compound (I).

[0027] The present invention has no special requirements on the source of the main raw material compound (VII), which can be commercially available or prepared according to the prior art.

[0028] In the preparation method of the compound (I) provided by the invention, the compound (III) as a reaction by-product can be isolated separately, and converted into the target compound (I) through further reaction; the compound (III) can also be separated without isolation, And together with compound (II) under the same reaction conditions, it can be converted into compound (I) at the same time.

[0029] But preferably compound (III) and compound (II) are not separated, but are converted into compound (I) simultaneously under the same reaction condit...

Embodiment 1

[0053] Compound (VII) (10 g), tert-butanol (300 mL), triethylamine (7.9 g) and diphenylphosphoryl azide (11.2 g) were added to a 500 mL reaction flask. Stirring was started, the mixture was heated to reflux and maintained at reflux for 16 hours, then cooled to room temperature, the solvent was removed by evaporation under reduced pressure, the residue was treated with water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The extracts were combined, washed with brine (150 mL), dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude product (12.1 g).

Embodiment 2

[0055] The crude product (12.1 g) obtained in Example 1 was purified by chromatography (silica gel, eluting with ethyl acetate containing 2% ethanol) to obtain two components, which were recrystallized from ether-hexane respectively to obtain a solid compound ( II) (5.25g) and solid compound (III) (3.76g).