Preparation method of flumatinib intermediate

Abstract

The invention relates to a preparation method of a flumatinib intermediate, and particularly relates to a synthesis process of an antitumor drug flumatinib intermediate. The preparation method specifically comprises the steps of firstly, synthesizing 4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide(III); secondly, synthesizing 5-bromine-2-methyl-3-nitropyridine(VI); and thirdly, synthesizing N-(6-methyl-5-nitropyridine-3-yl)-4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide(VII). The invention aims to provide a preparation method of the flumatinib intermediate,which is simple to operate, available in raw materials, short in reaction steps, high in yield and environment-friendly.

Description

technical field

[0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing a flumatinib intermediate. Background technique

[0002] Flumatinib, chemical name: 4-[(4-methyl-1-piperazinyl)methyl]-N-[6-methyl-5-[[4-(3-pyridyl)-2- Pyrimidinyl]amino]pyridin-3-yl]-3-(trifluoromethyl)-benzamide, a small molecule protein tyrosine kinase (PTK) inhibitor. By inhibiting the activity of Bcr-Abl tyrosine kinase, it inhibits the proliferation of tumor cells in Philadelphia chromosome-positive CML and some patients with acute lymphoblastic leukemia, and induces tumor cell apoptosis.

[0003] Its structural formula is:

[0004]

[0005] At present, there are few routes for the synthesis of flumatinib reported in the literature, and the literature that can be retrieved includes the literature of Xu Gang et al. (Synthetic Communications, 2010, vol.40, #17, p.2564-2570).

[0006]

[0007] This document has defects such as long steps, cumber...

Examples

Embodiment 1

[0031] Synthesis of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (III)

[0032]

[0033] Add compound I (50.0g, 1.0eq), compound II (23.8g, 1.5eq) and pyridine (100ml) into the reaction flask, raise the temperature to 110-115°C, and keep the reaction for 2-3 hours. Cool down to 20-30°C, add ammonia water (200ml), stir and crystallize for 2-3 hours. After filtering, the filter cake was washed with a small amount of water, and vacuum-dried at 50° C. for 15-16 hours to obtain 46.9 g of off-white solid, yield 94.2%, HPLC: 98.6%. MS (ESI) m / z: [M+H] = 302.04.

Embodiment 2

[0035] Synthesis of 5-bromo-2-methyl-3-nitropyridine (VI)

[0036]

[0037] Add diethyl malonate (120g, 2.0eq) into N,N-dimethylformamide (800ml), cool down to -10~0°C, add sodium hydride (25.5g, 3.4eq) in batches, add Stir for 15 minutes, then add 5-bromo-2-chloro-3-nitropyridine (160g, 2.0eq), transfer to room temperature and react for 2-4 hours, add water to quench, and extract with ethyl acetate, add anhydrous sodium sulfate to dry , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 2-(5-bromo-3-nitropyridin-2-yl)diethyl malonate, which was directly cast into the next step.

[0038] Add diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate obtained in the previous step into 6N hydrochloric acid (640ml), heat to reflux for 16-18 hours, spread diatomaceous earth and filter, The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate (1 L), washed with brine, dried over anhydrous sodium sulfat...

Embodiment 3

[0040] Example 3 Synthesis of N-(6-methyl-5-nitropyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl) Benzamide (III)

[0041]

[0042] Compound III (3.6g, 1.2eq), compound VI (2.17g, 1.0eq), CuI (0.38g, 0.2eq), potassium carbonate (3.46g, 2.5eq), N,N'-dimethylethanedi Add amine (0.18g, 0.2eq) and 1,4-dioxane (12ml) into the reaction flask, replace with nitrogen three times, raise the temperature to 90-100°C under the protection of nitrogen, and keep the reaction for 20-24 hours. Cool down to 20-30°C, add ammonia water (10ml) diluted twice, stir and crystallize for 2-3 hours. After filtering, the filter cake was washed with a small amount of water, and vacuum-dried at 50° C. for 15-16 hours to obtain 3.92 g of a brownish-yellow solid, with a molar yield of 89.7%, and HPLC: 99.3%.

[0043] MS (ESI) m / z: [M+H] = 438.1;

[0044] 1 H NMR (400MHz, [D6]DMSO, 23℃, TMS): δ11.00(s, 1H), 9.11(s, 1H), 8.90(s, 1H), 8.28(t, J=8.0Hz, 2H) ,7.95-7.97(d,J=8.0Hz,1H),3.70...

technical field

[0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing a flumatinib intermediate. Background technique

[0002] Flumatinib, chemical name: 4-[(4-methyl-1-piperazinyl)methyl]-N-[6-methyl-5-[[4-(3-pyridyl)-2- Pyrimidinyl]amino]pyridin-3-yl]-3-(trifluoromethyl)-benzamide, a small molecule protein tyrosine kinase (PTK) inhibitor. By inhibiting the activity of Bcr-Abl tyrosine kinase, it inhibits the proliferation of tumor cells in Philadelphia chromosome-positive CML and some patients with acute lymphoblastic leukemia, and induces tumor cell apoptosis.

[0003] Its structural formula is:

[0004]

[0005] At present, there are few routes for the synthesis of flumatinib reported in the literature, and the literature that can be retrieved includes the literature of Xu Gang et al. (Synthetic Communications, 2010, vol.40, #17, p.2564-2570).

[0006]

[0007] This document has defects such as long steps, cumber...

Examples

Embodiment 1

[0031] Synthesis of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (III)

[0032]

[0033] Add compound I (50.0g, 1.0eq), compound II (23.8g, 1.5eq) and pyridine (100ml) into the reaction flask, raise the temperature to 110-115°C, and keep the reaction for 2-3 hours. Cool down to 20-30°C, add ammonia water (200ml), stir and crystallize for 2-3 hours. After filtering, the filter cake was washed with a small amount of water, and vacuum-dried at 50° C. for 15-16 hours to obtain 46.9 g of off-white solid, yield 94.2%, HPLC: 98.6%. MS (ESI) m / z: [M+H] = 302.04.

Embodiment 2

[0035] Synthesis of 5-bromo-2-methyl-3-nitropyridine (VI)

[0036]

[0037] Add diethyl malonate (120g, 2.0eq) into N,N-dimethylformamide (800ml), cool down to -10~0°C, add sodium hydride (25.5g, 3.4eq) in batches, add Stir for 15 minutes, then add 5-bromo-2-chloro-3-nitropyridine (160g, 2.0eq), transfer to room temperature and react for 2-4 hours, add water to quench, and extract with ethyl acetate, add anhydrous sodium sulfate to dry , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 2-(5-bromo-3-nitropyridin-2-yl)diethyl malonate, which was directly cast into the next step.

[0038] Add diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate obtained in the previous step into 6N hydrochloric acid (640ml), heat to reflux for 16-18 hours, spread diatomaceous earth and filter, The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate (1 L), washed with brine, dried over anhydrous sodium sulfat...

Embodiment 3

[0040] Example 3 Synthesis of N-(6-methyl-5-nitropyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl) Benzamide (III)

[0041]

[0042] Compound III (3.6g, 1.2eq), compound VI (2.17g, 1.0eq), CuI (0.38g, 0.2eq), potassium carbonate (3.46g, 2.5eq), N,N'-dimethylethanedi Add amine (0.18g, 0.2eq) and 1,4-dioxane (12ml) into the reaction flask, replace with nitrogen three times, raise the temperature to 90-100°C under the protection of nitrogen, and keep the reaction for 20-24 hours. Cool down to 20-30°C, add ammonia water (10ml) diluted twice, stir and crystallize for 2-3 hours. After filtering, the filter cake was washed with a small amount of water, and vacuum-dried at 50° C. for 15-16 hours to obtain 3.92 g of a brownish-yellow solid, with a molar yield of 89.7%, and HPLC: 99.3%.

[0043] MS (ESI) m / z: [M+H] = 438.1;

[0044] 1 H NMR (400MHz, [D6]DMSO, 23℃, TMS): δ11.00(s, 1H), 9.11(s, 1H), 8.90(s, 1H), 8.28(t, J=8.0Hz, 2H) ,7.95-7.97(d,J=8.0Hz,1H),3.70...

Images