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Preparation method of crizotinib

A crizotinib and pyrazolyl technology, applied in the field of preparation of crizotinib, can solve the problems of difficult separation, difficult industrial production, boron ester heat and acid instability, etc., and achieves good optical purity Effect

Active Publication Date: 2016-02-03
XIHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This synthetic route prepares crizotinib intermediate E through the condensation method of borate ester and halide, but there are following disadvantages in this route: 1. the preparation process of borate ester is complex; it is not easy for industrialized production; The acid is unstable and the purity is not easy to control; ③The condensation reaction yield is low and the separation is difficult

Method used

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  • Preparation method of crizotinib
  • Preparation method of crizotinib
  • Preparation method of crizotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] 1, the preparation of boronic acid compound (3)

[0042]

[0043] Add 4L of freshly steamed tetrahydrofuran into a 50L kettle, add 2.60Kg of 4-iodopyrazole compound (11), dissolve and add 10L of isopropylmagnesium chloride solution (3.0M) dropwise, and control the reaction temperature below 25°C. After the dropwise addition was completed, the mixture was stirred at room temperature for 12 hours. The completion of the reaction was monitored by TLC, and 3 L of tetrahydrofuran solution in which 2.34 Kg of trimethoxyborane (21) was dissolved was added dropwise to the reaction solution. Control the reaction temperature at about 25°C, and continue stirring for 12 hours after the dropwise addition is completed. After the completion of the reaction monitored by TLC, the reaction was quenched with saturated aqueous ammonium chloride solution. Ethyl acetate was added, the layers were separated, and the organic layer was taken. The organic layer was washed successively with ...

Embodiment 2

[0051] 1, the preparation of boronic acid compound (3)

[0052]

[0053] Add 4L of freshly steamed tetrahydrofuran into a 50L kettle, add 1.9Kg of 4-bromopyrazole compound (12), dissolve and add 10L of isopropylmagnesium chloride solution (3.0M) dropwise. Stir at room temperature for 12 hours. After TLC monitored the completion of the reaction, 3 L of a tetrahydrofuran solution of 1.2 Kg of methoxyboronic acid pinacol ester (22) was added dropwise. After the dropwise addition was complete, stirring was continued for 12 hours. After the completion of the reaction monitored by TLC, it was quenched with saturated aqueous ammonium chloride. Ethyl acetate was added, and the layers were separated; the organic layer was washed with saturated aqueous sodium bicarbonate and water, and then concentrated to obtain 1.8Kg of solid.

[0054] 2. Preparation of Boc-crizotinib (5)

[0055]

[0056] Add 200g of boric acid compound (3), 100g of brominated compound (4) and 2g of phase t...

Embodiment 3

[0061] 1, the preparation of boronic acid compound (3)

[0062]

[0063] Add 4L of freshly steamed tetrahydrofuran into a 50L kettle, add 2.60Kg of 4-iodopyrazole compound (11), dissolve and add 10L of isopropylmagnesium chloride solution (3.0M) dropwise. Stir at room temperature for 12 hours. After TLC monitored the completion of the reaction, 3 L of tetrahydrofuran solution of 2.34 Kg isopropoxy pinacol borate (23) was added dropwise. After the dropwise addition was complete, stirring was continued for 12 hours. After the completion of the reaction monitored by TLC, it was quenched with saturated aqueous ammonium chloride. Ethyl acetate was added, and the layers were separated; the organic layer was washed with saturated aqueous sodium bicarbonate and water, and then concentrated to obtain 2.7Kg of solid.

[0064] 2. Preparation of Boc-crizotinib (5)

[0065]

[0066] Add 200g of boric acid compound (3), 100g of brominated compound (4) and 2g of phase transfer cata...

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Abstract

The invention discloses a preparation method of crizotinib. An intermediate (V) is prepared through boric acid condensation, so that the defects of instable borate serving as a raw material, complexity in operation, low yield and large-scale production difficulty in the prior art are overcome. The preparation method is low in cost, simple and convenient to operate, high in yield, good in optical purity and suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of crizotinib. Background technique [0002] Crizotinib (CAS877399-52-5, molecular formula: C 21 h 22 Cl 2 FN 5 O; molecular weight: 449.12; white powder) is an ATP-competitive small molecule inhibitor with c-Met kinase catalytic activity and high oral bioavailability. It can effectively inhibit the phosphorylation of c-Met and effectively inhibit c-Met-dependent cell proliferation, migration and invasion in vitro (IC 50 In addition, it can effectively inhibit the proliferation and invasion of endothelial cells stimulated by HGF and the angiogenesis induced by serum stimulation. Crizotinib is well tolerated, and its anti-tumor activity is dose-dependent (Cancer Res., 2007, 67(9):44082-44171), and is an important drug. [0003] [0004] Currently, US patents (WO2006021881A2, WO2007066187A2, WO2009036404A2) and domestic patents (CN101735198A, CN201210009870.6) have reported the synthesis route of cri...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCY02P20/55C07D401/14
Inventor 王周玉吴鹏程蒋珍菊钱珊杨羚羚翁光林刘斯宇谭平王伟徐志宏
Owner XIHUA UNIV
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