Preparation method for crizotinib

A compound and reaction technology, applied in the field of preparation of crizotinib, can solve the problems of low reaction yield, many reaction by-products, etc., and achieve the effects of short reaction route, shortened reaction period and environmental protection

Active Publication Date: 2014-08-20
RAYBOW (HANGZHOU) PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In this method, the free amino group of the reaction intermediate compound 5-bromo-3(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-amino-pyridine is not protected, and there are many reaction by-products , after the reaction is completed, column chromatography is required for purification, and the reaction yield is low, only 61% after purification

Method used

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  • Preparation method for crizotinib
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  • Preparation method for crizotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Preparation of 5-bromo-3-hydroxyl-2-tert-butoxycarbonylaminopyridine

[0050] In 2-amino-3-hydroxy-5-bromopyridine (10.0g, 53.0mmol) and Et 3 N (10mL, 71.8mmol) in dichloromethane (100mL) solution, add Boc 2 O (12.7 g, 58.4 mmol). The reaction was stirred at room temperature for 18 h. Add 150 mL of water to the mixture, continue to stir for 30 min, filter the insoluble matter through celite, separate the organic phase, and extract with 150 mL of dichloromethane. The combined organic phases were washed with saturated NaCl solution (2 × 100 mL), followed by anhydrous NaCl 2 SO 4 dry. The solvent was removed under reduced pressure, EtOAc (200 mL) was added to the residue until dissolved, then activated carbon (2.0 g) was added, and stirred at room temperature for 30 min. Filter through diatomaceous earth, remove the solvent from the filtrate under reduced pressure, add hexane (100 mL) to the residue to make a slurry, filter, and dry in vacuo to obtain 15.0...

Embodiment 2

[0052] Example 2: Preparation of 5-bromo-3(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butoxycarbonylamino-pyridine

[0053] Under nitrogen atmosphere, 1-(2,6-dichloro-3-fluorophenyl)ethanol (1.0g, 4.78mmol), 5-bromo-3-hydroxyl-2-tert-butoxycarbonylaminopyridine (1.4g , 4.78mmol) and triphenylphosphine (1.6g, 6.2mmol) were dissolved in 20mL of anhydrous THF and cooled to below 0°C. Then, diisopropyl azodicarboxylate (1.25 g, 6.2 mmol) was added dropwise, controlling the temperature to <5°C. The mixture was stirred at room temperature for 6 hours. Filter and remove the solvent under reduced pressure to obtain an oily substance, which is recrystallized with ethanol to obtain a white solid 5-bromo-3(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert Butoxycarbonylamino-pyridine 2.13g, yield 93.0%.

[0054] 1 H NMR (400MHz, CDCl 3 ):δ8.05(d,J=1.6Hz,1H),7.51(brs,1H),7.32(dd,J=4.8Hz,4.4Hz,1H),7.12-7.08(m,2H),6.05(q ,J=6.4Hz,1H),1.85(d,J=6.4Hz,3H),1.55(s,9H);

Embodiment 3

[0055] Example 3: 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-1H Preparation of -pyrazol-4-yl]-2-tert-butoxycarbonylamino-pyridine

[0056] 5-Bromo-3(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butoxycarbonylamino-pyridine (0.24g, 0.5mmol) and 4-[4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-1-tert-butoxycarbonyl-piperidine (0.19g, 0.5mmol) was dissolved in 5mL DMF, added with Na 2 CO 3 (0.16g, 1.5mmol) in 1mL aqueous solution, add Pd(Ph 3 P) 2 Cl 2 (8.8mg, 0.0125mmol), the reaction mixture was heated to 60°C and stirred for 6 hours under a nitrogen atmosphere, then cooled to room temperature, filtered to remove insoluble matter, and extracted with methyl tert-butyl ether (3×5mL). The combined organic phases were washed with saturated NaCl solution (2 × 5 mL), followed by anhydrous NaCl 2 SO 4 dry. The solvent was removed under reduced pressure to give white solid 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]...

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Abstract

The present invention relates to the field of pharmaceutical synthesis, in particular to a crizotinib preparation method. The method is a preparation method of a compound having a structure of formula (a): conducting Suzuki coupling reaction between a compound having a structure of formula (b) and a compound having a structure of formula (e) to obtain the compound having the structure of formula (a); further conducting a deprotection reaction on the compound having the structure of formula (a) to obtain (±) crizotinib.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of crizotinib. Background technique [0002] Crizotinib is a new drug of Pfizer for the treatment of lung cancer. It is the first drug targeting anaplastic lymphoma kinase (ALK), and it can be used to treat ALK-positive locally advanced or metastatic non-cancerous tumors. Small Cell Lung Cancer. Its chemical name is: 3-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyridine Azol-4-yl]pyridin-2-amine. [0003] [0004] At present, the preparation methods of crizotinib mainly include: for example, the patent application US20060128724 published by Pfizer Corporation of the United States: [0005] method one: [0006] [0007] The method has a long reaction route, and the amino group in the intermediate compound 5-bromo-3(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-amino-pyridine is protected during the reaction , need to add...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14C07D213/75
Inventor 李原强钱建强车大庆
Owner RAYBOW (HANGZHOU) PHARM CO LTD
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