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Synthetic method for crizotinib intermediate

A technology of crizotinib and a synthetic method, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of difficult large-scale industrial production, expensive enzyme catalysts, harsh reaction conditions, etc., and achieve good application prospects, easy purchase, Quality Controlled Effects

Inactive Publication Date: 2015-03-11
SUZHOU JONATHAN NEW MATERIALS TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this method are: 1. The enzyme-catalyzed reaction of compound A2 takes a long time and the reaction conditions are harsh; 2. The reaction yield is low, the operation is complicated, and the experiment reproducibility is poor; 3. The enzyme catalyst is expensive; 4. It is difficult to produce on a large scale

Method used

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  • Synthetic method for crizotinib intermediate
  • Synthetic method for crizotinib intermediate
  • Synthetic method for crizotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add compound (I) 2,6-dichloro-3-fluoroacetophenone (100g, 0.488mol, 1eq), tetrahydrofuran (10L) to the dry reaction flask, start stirring, cool to 0 degrees Celsius under nitrogen protection, drop (-)DIP-Cl (60% W / W n-heptane solution, 651.5g, 1.22mol, 2.5eq), the dropwise addition was completed within 90 minutes, slowly raised to 25 degrees Celsius, stirred for 15 hours, followed by HPLC, the reaction was complete, 0 degrees Celsius Slowly add saturated sodium bicarbonate solution, adjust the pH to about 7, let the layers stand still, and evaporate the organic solvent. After the residue is cooled to room temperature, add 6L of n-hexane, stir at room temperature for 1 hour, place in the refrigerator overnight, and filter while cold. The filter cake was washed with 1 L of iced n-hexane to obtain a white solid, crizotinib intermediate compound (II) (95 g, yield 94%, ee98%).

Embodiment 2

[0025] Add compound (I) 2,6-dichloro-3-fluoroacetophenone (100g, 0.488mol, 1eq), tetrahydrofuran (10L) to the dry reaction flask, start stirring, cool to 0 degrees Celsius under nitrogen protection, drop (-)DIP-Cl (60% W / W n-heptane solution, 391g, 0.73mol, 1.5eq), the dropwise addition was completed within 60 minutes, slowly raised to 25 degrees Celsius, stirred for 15 hours, the reaction was complete after HPLC tracking, and the reaction was slow at 0 degrees Celsius Slowly add saturated sodium bicarbonate solution, adjust the pH to about 7, let the layers stand still, and evaporate the organic solvent. After the residue is cooled to room temperature, add 6L of n-hexane, stir at room temperature for 1 hour, place in the refrigerator overnight, and filter while cold. The cake was washed with 1 L of iced n-hexane to obtain a white solid, crizotinib intermediate compound (II) (75 g, yield 74%, ee88%).

Embodiment 3

[0027] Add compound (I) 2,6-dichloro-3-fluoroacetophenone (100g, 0.488mol, 1eq), tetrahydrofuran (10L) to the dry reaction flask, start stirring, cool to 0 degrees Celsius under nitrogen protection, drop (-)DIP-Cl (60% W / W n-heptane solution, 781.8g, 1.46mol, 3eq), the dropwise addition was completed within 90 minutes, slowly raised to 25 degrees Celsius, stirred for 15 hours, the reaction was complete after HPLC tracking, and the reaction was slow at 0 degrees Celsius Slowly add saturated sodium bicarbonate solution, adjust the pH to about 7, let the layers stand still, and evaporate the organic solvent. After the residue is cooled to room temperature, add 6L of n-hexane, stir at room temperature for 1 hour, place in the refrigerator overnight, and filter while cold. The cake was washed with 1 L of iced n-hexane to obtain a white solid, crizotinib intermediate compound (II) (90 g, yield 89%, ee93%).

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Abstract

The invention provides a synthetic method for a crizotinib intermediate. The method comprises the following steps: (1), obtaining a crude product through reaction of a compound (I) namely 2,6-dichloro-3-fluoroacetophenone and (-) DIP-Cl in an organic solvent at the temperature of 0-25 DEG C; (2), re-crystallizing the crude product obtained in the step (1) by using normal hexane to obtain a crizotinib intermediate compound (II). A key intermediate is synthesized at one step by using an asymmetric catalysis method, and is controllable in quality, simple and convenient to operate, high in yield, high in optical purity and applicable to industrial production. A reaction structure formula of the method is shown as follows.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, more particularly to a synthesis method of crizotinib intermediates. Background technique [0002] Crizotinib (crizotinib, 1), the chemical name is 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4- Piperidinyl)-1H-pyrazol-4-yl]-2-aminopyridine is developed by Pfizer for the treatment of anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer ( The small molecule kinase inhibitor of NSCLC is currently the only drug for the treatment of this type of disease. In August 2011, it was approved by the FDA for marketing in the United States, and then it was marketed in South Korea, Japan, and the European Union. In January 2013, it was approved by the SFDA for marketing in China. ,Product name (The Chinese product name is Serek). This product targets ALK, hepatocyte growth factor receptor (c-met, HGFR) and tyrosine kinase rec...

Claims

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Application Information

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IPC IPC(8): C07C33/46C07C29/143
CPCC07C29/143
Inventor 李卓才李苏杨
Owner SUZHOU JONATHAN NEW MATERIALS TECH
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