Method for synthesizing Crizotinib intermediate

A technology for crizotinib and intermediates, applied in the field of synthesizing crizotinib intermediates, can solve the problems of high cost, high preparation cost of reaction substrate iodide, difficult industrialized production and the like, and achieves reduction in preparation cost, It is convenient for industrial production and application, and the preparation cost is low.

Inactive Publication Date: 2013-01-30
TONGJI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Existing methods all utilize the Miyaura boration method to synthesize boroester compounds 1 , expensive palladium catalysts and ligands need to be used in the reaction, and the preparation cost of the reaction substrate iodide is also

Method used

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  • Method for synthesizing Crizotinib intermediate
  • Method for synthesizing Crizotinib intermediate
  • Method for synthesizing Crizotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]

[0046] Add 4-nitropyrazole (3.73 g, 0.033 mol) and 80 mL of N,N-dimethylformamide into the reactor. Cool in an ice bath to 0°C, stir, add sodium hydride (0.93 g, 0.038 mol) in batches, stir at the same temperature for 1 h after addition, add compound 2 (10.0 g, 0.036 mol) to the reaction solution, heat up to 100°C, and react for 12 h . Cool, add 400 mL of water, extract three times with 400 mL of ethyl acetate, dry over anhydrous sodium sulfate, filter and spin dry to obtain the crude product, recrystallize from ethyl acetate petroleum ether to obtain the compound 3 (7.8 g yield 80%).

Embodiment 2

[0048]

[0049] Add 4-nitropyrazole (3.73 g, 0.033 mol) and 100 mL of dimethyl sulfoxide to the reactor. Cool in an ice bath to 0°C, stir, add potassium hydroxide (0.93 g, 0.038 mol) in batches, stir at the same temperature for 1 h after addition, add compound 2 (10 g, 0.036 mol) to the reaction solution, raise the temperature to 80°C, and react 18 h. Cool, add 400 mL of water, extract three times with 400 mL of ethyl acetate, dry over anhydrous sodium sulfate, filter and spin dry to obtain the crude product, recrystallize from ethyl acetate petroleum ether to obtain the compound 3 (7.1 g yield 72%).

Embodiment 3

[0051]

[0052] Add 4-nitropyrazole (3.73 g, 0.033 mol) and 80 mL of toluene into the reactor. Cool in an ice bath to 5 °C, stir, add potassium tert-butoxide (0.93 g, 0.038 mol) in batches, stir at the same temperature for 1 h after addition, add compound to the reaction solution 2 (10 g, 0.036 mol), heated up to 108°C, and reacted for 10 h. Cool, add 400 mL of water, separate the layers, extract three times with 400 mL of ethyl acetate, dry over anhydrous sodium sulfate, filter and spin dry to obtain the crude product, recrystallize from ethyl acetate / petroleum ether to obtain the compound 3 (7.4 g yield 76%).

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Abstract

The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for synthesizing a Crizotinib intermediate. The method comprises steps of: a) reacting a raw material 4-mesylate piperidine-1-formic acid tert-butyl ester (2) with 4-nitro pyrazole to prepare a compound 3; b) reducing nitro by using hydrazine hydrate to obtain an amino compound 4; and c) diazotizing the compound 4 by using tert-butyl nitrite, and reacting the compound 4 with a boric acid ester compound 5 in the presence of a free radical initiator benzoyl peroxide, so as to prepare the Crizotinib intermediate (1). Compared with an existing synthesis method, the method provided by the invention has the following advantages: a diazotization method is used to synthesize the boric acid ester product; and compared with an existing Miyaura boronation method catalyzed by Pd, the method avoids the usage of expensive palladium catalyst and ligand, and has the merits of mild reaction condition, high yield, simple operation, cheap and easily available raw materials and short reaction period, and is quite easy for industrialized mass production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing a crizotinib intermediate (compound 1). Background technique [0002] Crizotinib is a new drug (WO 2006021881, EP 1784396, CN 1010187800) developed by Pfizer for the treatment of non-small cell lung cancer (accounting for 80-85% of the total lung cancer). Approved by the US FDA for marketing. English product name is Xalko, Chinese chemical name: 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl) -1H-pyrazol-4-yl]-2-pyridinamine; English chemical name: (R)-3-[1-(2,6-dichloro-3-fluorophenyl)–ethoxy-5-(1-piperidin- 4-yl-1H–pyrazol-4-yl)-pyridin-2-ylamine. [0003] The molecular structural formula is as follows: [0004] [0005] Crizotinib [0006] Crizotinib is mainly used for the treatment of anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (non-small-cell lung ...

Claims

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Application Information

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IPC IPC(8): C07F5/02
Inventor 匡春香王卓
Owner TONGJI UNIV
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