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Homogeneous-phase 'one-pot' preparation method of Brigatinib key intermediate

An intermediate and key technology, applied in the field of homogeneous "one-pot" preparation, can solve the problems of incomplete reaction, low yield, cumbersome operation, etc., achieve high efficiency and yield, reduce solvent consumption, and shorten steps Effect

Active Publication Date: 2017-12-29
CHANGZHOU VOCATIONAL INST OF ENG
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The above-mentioned synthesis method about (II) has obvious defects in the actual process: 1) the synthesis process of intermediate (IV) has incomplete reaction and low efficiency, and requires column chromatography purification
2) The yield is not high, the total yield of the two-step reaction is only 49.9% (J.Med.Chem.2016,59,4948-4964), and the operation process is complicated, time-consuming and laborious, which is not conducive to industrial production
[0010] As can be seen from the above, the prior art has the defects of low yield, low efficiency and cumbersome operation, which is an important factor affecting the industrial production of Brigatinib intermediate (II) at present

Method used

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  • Homogeneous-phase 'one-pot' preparation method of Brigatinib key intermediate
  • Homogeneous-phase 'one-pot' preparation method of Brigatinib key intermediate
  • Homogeneous-phase 'one-pot' preparation method of Brigatinib key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Add 2-iodoaniline (17.5g, 79.9mmol) and dimethylphosphine oxide (6.9g, 88.5mmol), palladium acetate (0.3g, 1.3mmol), Xantphos (0.77g, 1.3mmol), N,N-di Isopropylethylamine (22.7g, 175.8mmol), DMF (50mL), magnetic stirring. Under the protection of nitrogen, it was heated to 100°C for 6 hours, and the 2-iodoaniline was completely consumed as monitored by thin-layer chromatography. Cool to room temperature, add 2,4,5-trichloropyrimidine (17.5 g, 95.9 mmol), heat to 75 ° C for 6 hours, and monitor the completion of the reaction by thin-layer chromatography. Cool to room temperature, add 300 mL of water, adjust pH to 5 with 5% hydrochloric acid, extract with ethyl acetate (100 mL×3), wash with sodium bicarbonate solution (100 mL), wash with saturated sodium chloride solution (100 mL×2), anhydrous sulfuric acid Sodium dry. Suction filtration and concentration gave a crude brown solid, which was recrystallized from ethyl acetate / petroleum ether (volume ratio 1:2) to obtain 17...

Embodiment 2

[0025] Add 2-iodoaniline (8.6g, 39.3mmol) and dimethylphosphine oxide (3.4g, 43.6mmol), tetrakis (triphenylphosphine) palladium (0.92g, 0.8mmol), N,N-diisopropyl Ethylamine (11.2g, 86.7mmol), DMF (30mL), magnetic stirring. Under the protection of nitrogen, it was heated to 90°C for 8 hours, and the 2-iodoaniline was completely consumed as monitored by thin-layer chromatography. Cool to room temperature, add 2,4,5-trichloropyrimidine (8.6g, 47.0mmol), heat to 75°C for 6 hours, and monitor the completion of the reaction by thin-layer chromatography. Cool to room temperature, add 200 mL of water, adjust pH to 5 with 5% hydrochloric acid, extract with ethyl acetate (70 mL×3), wash with sodium bicarbonate solution (100 mL), wash with saturated sodium chloride solution (100 mL×2), anhydrous sulfuric acid Sodium dry. Suction filtration and concentration gave crude brown solid, which was recrystallized from ethyl acetate / petroleum ether (volume ratio 1:2) to obtain 6.8 g of off-whit...

Embodiment 3

[0027] Add 2-iodoaniline (7.8g, 35.6mmol) and dimethylphosphine oxide (3.1g, 39.7mmol), palladium acetate (0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), N,N-di Isopropylethylamine (9.2g, 71.2mmol), DMF (30mL), magnetic stirring. Under the protection of nitrogen, it was heated to 100°C for 6 hours, and the 2-iodoaniline was completely consumed as monitored by thin-layer chromatography. Cool to room temperature, add 2,4,5-trichloropyrimidine (7.8g, 42.7mmol), heat to 75°C for 6 hours, and monitor the completion of the reaction by thin-layer chromatography. Cool to room temperature, add 200 mL of water, adjust pH to 5 with 5% HCl, extract with ethyl acetate (70 mL×3), wash with sodium bicarbonate solution (100 mL), wash with saturated sodium chloride solution (100 mL×2), anhydrous sulfuric acid Sodium dry. Suction filtration and concentration gave a crude brown solid, which was recrystallized from ethyl acetate / petroleum ether (volume ratio 1:2) to obtain 6.6 g of a near-white ...

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a homogeneous-phase 'one-pot' preparation method of a Brigatinib key intermediate (II). The preparation method includes the steps: performing coupling reaction on 2-iodoaniline and dimethyl phosphine oxide under the action of catalysts and acid-binding agents; directly performing substitution reaction on reactants and 2, 4, 5-trichloropyrimidine without separation; performing extraction, washing, drying, filtration and concentration to obtain a crude product; performing recrystallization on the crude product to obtain a (2-((2,5-dichloropyrimidine-4-group) amidogen) phenyl) dimethyl phosphine oxide (II). According to the method, two-step reaction is replaced by a homogeneous-phase 'one-pot' method, separation and purification are omitted, steps are decreased, operation is simplified, yield is improved as compared with the prior art, recrystallization replaces column chromatography purification, solvent consumption and emission of 'waste gas, waste water and solid waste' are reduced, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a homogeneous "one-pot" preparation method for the key intermediate (II) of Brigatinib. Background technique [0002] Brigatinib, whose trade name is Alunbrig, was developed and marketed by Ariad Pharmaceuticals, which is now part of Takeda Pharmaceuticals. It was approved by the FDA in April 2017 for patients who have progressed after treatment with Crizotinib, or who cannot respond to Crizotinib. Resistant anaplastic lymphoma kinase-positive (ALK+) locally advanced or metastatic non-small cell lung cancer. In addition, indications under development include fibrosarcoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma, among others. According to statistics from ThomsonReuters, Brigatinib will achieve sales of US$45.33 million in 2017, and then increase year by year. By 2021, the annual sales will reach US$478 million, which has a v...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6512
Inventor 周海平邱岳进包小波刘巧云倪迎港
Owner CHANGZHOU VOCATIONAL INST OF ENG
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