Purification Method of Nilotinib Intermediate 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

Abstract

The present invention discloses a method for refining and purifying nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, which includes the steps of primary refining, salt formation, and free refining to obtain a qualified product of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate. This refining method is simple in operation and suitable for industrial production. The single impurity of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate obtained is ≤0.10%, and the ignition residue is less than 0.05%, which is beneficial to improving the product quality of nilotinib raw material drug.

Description

Technical Field

[0001] The present invention relates to the technical field of raw drug synthesis and intermediate purification, and particularly relates to a refining and purification method for nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. Background Art

[0002] Nilotinib (the compound shown in Formula I) is a highly selective oral tyrosine kinase inhibitor developed by Novartis Pharmaceuticals Corporation of Switzerland. Its monohydrochloride monohydrate was approved by the US FDA for marketing under the trade name Tasigna in October 2007 and is clinically used for chronic myeloid leukemia that is ineffective in imatinib treatment.

[0003] 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (as Figure 1 the compound shown in Formula II) is a key intermediate for synthesizing nilotinib. Most of the existing technologies for preparing this intermediate use 3-bromo-5-trifluoromethylaniline as a raw material and carry out an Ullmann coupling reaction with an excess of 4-methylimidazole in the presence of CuI, a ligand (such as 8-hydroxyquinoline, L-proline, N,N-dimethylglycine, N,N'-dimethylethylenediamine, etc.) and a base (such as potassium carbonate, cesium carbonate, etc.) to obtain it.

[0004] However, this preparation method has the following two problems:

[0005] 1) During the reaction process, about 10% of 5-position isomer impurities (such as Figure 2 the compound shown in Formula III) and 0.2 - 0.3% of ethyl homolog impurities (such as Figure 3 the compound shown in Formula IV) will be generated. Once these two impurities remain at a high level in this intermediate, it will cause the related substances of nilotinib raw drug to fail to meet the standards.

[0006] 2) The reaction uses 10 - 30% molar amount of cuprous iodide as a catalyst. If not properly treated, a large amount of copper ions will remain in this intermediate, resulting in the ignition residue of this intermediate being much higher than 0.10%, and ultimately may cause the copper element in nilotinib API to exceed the standard.

[0007] To ensure that the quality of the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline meets the usage requirements for producing nilotinib raw drug, it is necessary to develop a suitable refining and purification method for the crude product after the coupling reaction of the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline to control the 5-position isomer impurities and ethyl homolog impurities in this intermediate below 0.10%, and at the same time control the ignition residue below 0.10%. Summary of the Invention

[0008] In view of this, the object of the present invention is to provide a method for refining and purifying nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, so as to solve one or more of the above-mentioned problems in the prior art.

[0009] To achieve the above object, the present invention provides a method for refining and purifying nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, which comprises the following steps:

[0010] S1 primary refining: Mix the crude product or concentrate of the coupling reaction of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate with solvent A and solvent B, add disodium ethylenediaminetetraacetate (EDTA·2Na) and 25% concentrated ammonia water, heat up to 80 - 90 °C and stir for 3 - 5 hours, then cool down to 25 - 35 °C, keep warm for 1 - 2 hours and then filter, wash with clear water, and collect the material after suction filtration until the water content is less than 30% to obtain the primary refined crude product of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate;

[0011] S2 salt formation: Mix the primary refined crude product in step S1 with reaction solvent C, heat up to 60 - 65 °C, dropwise add hydrochloric acid to adjust the system pH = 2 - 3, then slowly cool down for crystallization, finally cool down to -5 ± 2 °C, keep warm for 3 - 5 hours and then filter, wash with solvent C pre-cooled at -10 - -5 °C, and dry under vacuum to collect the monohydrochloride salt of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate;

[0012] S3 free refining: Mix the monohydrochloride salt of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate in step S2 with 10 times the volume of solvent D, heat up to 70 - 80 °C, dropwise add dilute sodium bicarbonate aqueous solution to adjust the system pH ≥ 10, let it stand for liquid separation, collect the organic phase, concentrate under reduced pressure to 1 - 5 times the volume, then slowly cool down for crystallization, finally cool down to -10 - 10 °C, keep warm for 3 - 5 hours and then filter, wash with solvent D pre-cooled at -15 - -5 °C, and dry under vacuum to collect the qualified product of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate.

[0013] In some embodiments, the solvent A is selected from one of the three solvents of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably N,N-dimethylformamide, and the solvent B is water.

[0014] In some embodiments, in step S1, relative to the crude product or concentrate of the coupling reaction of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate, the dosage of solvent A is 1-4 vol, the dosage of solvent B is 8-12 vol, the molar feeding ratio of EDTA·2Na is 0.3-0.6 eq; the dosage of 25% concentrated ammonia water is 0.5-1.5 vol.

[0015] In some embodiments, the reaction solvent C is selected from one of the three solvents of absolute ethanol, isopropanol, and 2-butanone, and absolute ethanol is preferred.

[0016] In some embodiments, in step S2, relative to the first refined crude product of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate, the dosage of the reaction solvent C is 3-5 vol.

[0017] In some embodiments, the solvent D is selected from one of the four solvents of toluene, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether, and toluene is preferred.

[0018] In some embodiments, the crude product or concentrate of the coupling reaction of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate is prepared by the following steps:

[0019] Add 3-bromo-5-trifluoromethylaniline, DMF, anhydrous potassium carbonate, 4-methylimidazole, and sodium iodide to the reaction flask in sequence. After evacuating and replacing nitrogen three times, add copper iodide and the ligand N,N'-dimethylethylenediamine, heat up to 120°C - 130°C and stir the reaction until the raw materials are completely converted, cool down to room temperature, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the concentrate of the coupling reaction of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate.

[0020] In some embodiments, relative to 3-bromo-5-trifluoromethylaniline, the dosage of DMF is 6 Vol, the molar feeding ratio of anhydrous potassium carbonate is 2.0 eq, the molar feeding ratio of 4-methylimidazole is 2.0 eq, the molar feeding ratio of sodium iodide is 0.25 eq, the molar feeding ratio of copper iodide is 0.30 eq, and the molar feeding ratio of N,N'-dimethylethylenediamine is 0.60 eq.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] 1. The refining method of the present invention is simple in operation and suitable for industrial production;

[0023] 2. The single impurity of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate obtained by the purification method of the present invention is ≤0.10%, and the ignition residue is less than 0.05%, which is beneficial to improving the product quality of nilotinib API. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the synthesis route of nilotinib in the background art of the present invention;

[0025] Figure 2 is the structural formula of the compound shown in III in the background art of the present invention;

[0026] Figure 3 is the structural formula of the compound shown in IV in the background art of the present invention;

[0027] Figure 4 is the HPLC chromatogram of the qualified product of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate in Example 1 of the present invention;

[0028] Figure 5 is the HPLC chromatogram of the qualified product of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate in Example 2 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention will be described in detail below with reference to the accompanying drawings and specific examples.

[0030] Example 1:

[0031] S1 First refinement: Mix the coupling reaction concentrate (48 g) of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate with N,N-dimethylformamide (solvent A, 96 mL, 2 Vol) and water (solvent B, 480 mL, 10 Vol), add disodium ethylenediaminetetraacetate (0.5 eq, 33.48 g) and 25% concentrated ammonia water (36 mL, 0.75 Vol), heat up to 80 - 90 °C and stir for 4 hours, then cool down to 25 - 35 °C, keep warm for 2 hours and then filter, wash with clear water until the pH of the filtrate ≤ 9, and then suction filter until the water content is less than 30% to obtain 48 g of wet product of the first refined crude product of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate;

[0032] S2 Salt formation Mix all the wet products from the previous step with the reaction solvent 2-butanone (solvent C, 240 mL, 5 Vol), heat up to 60 - 65 °C, add hydrochloric acid dropwise to adjust the system pH to 2 - 3, then slowly cool down for crystallization. Finally, cool down to -5 ± 2 °C, keep warm for 3 - 5 hours and then filter. Wash with 2-butanone (24 mL, 0.5 Vol) pre-cooled to -10 - -5 °C, and dry in vacuum. 40.8 g of the monohydrochloride salt of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate is obtained as an off-white solid;

[0033] S3 Free and refine Mix all of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline monohydrochloride from the previous step with isopropyl acetate (solvent D, 408 mL, 10 Vol), heat up to 70 - 80 °C, add a mixed solution of sodium bicarbonate (18 g) and water (200 mL) dropwise to adjust the system pH ≥ 10, let it stand for liquid separation, collect the organic phase, concentrate under reduced pressure to 1.5 times the volume, then slowly cool down for crystallization. Finally, cool down to -5 - 5 °C, keep warm for 3.5 hours and then filter. Wash with isopropyl acetate (20 mL, 0.5 Vol) pre-cooled to -10 °C, and dry in vacuum. 33 g of the qualified product of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate is obtained as an off-white solid. The purity detected by HPLC is as Figure 4 shown, the purity is 99.97%, the 5-position isomer impurity is not detected, and the ethyl homolog impurity is 0.04%; the ignition residue is 0.02%.

[0034] Example 2:

[0035] S1 First refinement Mix the concentrated product of the coupling reaction of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate (48 g) with N,N-dimethylacetamide (solvent A, 72 mL, 1.5 Vol) and water (solvent B, 576 mL, 12 Vol), add disodium ethylenediaminetetraacetate (0.3 eq, 20 g) and 25% concentrated ammonia water (72 mL, 1.5 Vol), heat up to 80 - 90 °C and stir for 4 hours. Then cool down to 25 - 35 °C, keep warm for 2 hours and then filter. Wash with clear water until the filtrate pH ≤ 9, and then suction filter until the water content is less than 30% and then collect the material to obtain 44 g of the wet product of the crude product of the first refinement of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate;

[0036] S2 Salt formation Mix all the wet products from the previous step with anhydrous ethanol (solvent C, 176 mL, 4 Vol) as the reaction solvent, heat up to 60 - 65 °C, add hydrochloric acid dropwise to adjust the system pH to 2 - 3, then slowly cool down for crystallization. Finally, cool down to -5 ± 2 °C, keep warm for 3 - 5 hours and then filter, wash with anhydrous ethanol (48 mL, 1.0 Vol) pre-cooled to -10 - -5 °C, and dry under vacuum. Collect 39 g of the monohydrochloride of the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, which is an off-white solid.

[0037] S3 Free purification Mix all of the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline monohydrochloride from the previous step with toluene (solvent D, 390 mL, 10 Vol), heat up to 70 - 80 °C, add a mixed solution of sodium bicarbonate (18 g) and water (200 mL) dropwise to adjust the system pH ≥ 10, let it stand for layer separation, collect the organic phase, concentrate under reduced pressure to 4 times the volume, then slowly cool down for crystallization. Finally, cool down to -5 - 5 °C, keep warm for 3.5 hours and then filter, wash with toluene (59 mL, 1.5 Vol) pre-cooled to -10 °C, and dry under vacuum. Collect 31.5 g of the qualified product of the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, which is an off-white solid. The purity detected by HPLC is as Figure 5 shown. The purity is 99.97%, the 5-position isomer impurity is not detected, and the ethyl homolog impurity is 0.03%; the ignition residue is 0.02%. The purity is 99.98%, the 5-position isomer impurity is not detected, and the ethyl homolog impurity is 0.02%; the ignition residue is 0.01%.

[0038] The embodiment of the present invention provides a purification method for the nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, and this purification method has the following advantages:

[0039] 1. The purification method of the present invention is simple to operate and suitable for industrial production;

[0040] 2. For the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline obtained by the purification method of the present invention, the individual impurity ≤ 0.10%, and the ignition residue is lower than 0.05%, which is beneficial to improving the product quality of nilotinib API.

[0041] Finally, it should be noted that those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments. The above embodiments and the description in the specification only illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for refining and purifying nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, characterized in that, It includes the following steps: S1 First refinement: Mix the crude product or concentrate of the coupling reaction of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate with solvent A and solvent B, add disodium ethylenediaminetetraacetate (EDTA·2Na) and 25% concentrated ammonia water, heat up to 80-90 °C and stir for 3-5 hours, then cool down to 25-35 °C, keep warm for 1-2 hours and then filter, wash with clear water, and collect the material after suction filtration until the water content is less than 30% to obtain the first-refined crude product of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate; S2 Salt formation: Mix the first-refined crude product in step S1 with reaction solvent C, heat up to 60-65 °C, dropwise add hydrochloric acid to adjust the system pH = 2-3, then slowly cool down for crystallization, finally cool down to -5±2 °C, keep warm for 3-5 hours and then filter, wash with solvent C pre-cooled at -10~-5 °C, dry under vacuum, and collect the material to obtain the monohydrochloride salt of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate; S3 Free and refined: Mix the monohydrochloride salt of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate in step S2 with 10 times the volume of solvent D, heat up to 70-80 °C, dropwise add dilute sodium bicarbonate aqueous solution to adjust the system pH ≥10, let it stand for liquid separation, collect the organic phase, concentrate under reduced pressure to 1-5 times the volume, then slowly cool down for crystallization, finally cool down to -10~10 °C, keep warm for 3-5 hours and then filter, wash with solvent D pre-cooled at -15~-5 °C, dry under vacuum, and collect the material to obtain the qualified product of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate; Among them, the crude product or concentrate of the coupling reaction of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate is prepared by the following steps: Add 3-bromo-5-trifluoromethylaniline, DMF, anhydrous potassium carbonate, 4-methylimidazole and sodium iodide into the reaction flask in sequence. After evacuating and replacing nitrogen three times, add copper iodide and ligand N,N'-dimethylethylenediamine, heat up to 120 °C~130 °C and stir for reaction until the raw materials are completely converted, cool down to room temperature, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the concentrate of the coupling reaction of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate.

2. The refining and purification method according to claim 1, characterized in that, The solvent A is selected from one of the three solvents of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and the solvent B is water.

3. The refining and purification method according to claim 2, characterized in that, The solvent A is N,N-dimethylformamide.

4. The refining and purification method according to claim 1, wherein In step S1, relative to the crude product or concentrate of the coupling reaction of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline intermediate, the dosage of solvent A is 1-4 vol, the dosage of solvent B is 8-12 vol, the molar feeding ratio of EDTA·2Na is 0.3-0.6 eq; the dosage of 25% concentrated ammonia water is 0.5-1.5 vol.

5. The refining and purification method according to claim 1, characterized in that, The reaction solvent C is selected from one of the three solvents: absolute ethanol, isopropanol, and 2-butanone.

6. The refining and purification method according to claim 5, characterized in that, The reaction solvent C is absolute ethanol.

7. The refining and purification method according to claim 1, characterized in that, In the step S2, relative to the crude and fine product of the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, the dosage of the reaction solvent C is 3 - 5 vol.

8. The refining and purification method according to claim 1, characterized in that, The solvent D is selected from one of the four solvents: toluene, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether.

9. The refining and purification method according to claim 1, wherein, Relative to 3-bromo-5-trifluoromethylaniline, the dosage of DMF is 6 Vol, the molar feeding ratio of anhydrous potassium carbonate is 2.0eq, the molar feeding ratio of 4-methylimidazole is 2.0eq, the molar feeding ratio of sodium iodide is 0.25eq, the molar feeding ratio of copper iodide is 0.30 eq, and the molar feeding ratio of N,N'-dimethylethylenediamine is 0.60 eq.

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