Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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
View PDF4 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 high; at the same time, the reaction conditions are harsh and need to be reacted under highly anhydrous and oxygen-free conditions, the cost is high and the operation is cumbersome, so This route is difficult to apply to industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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%).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07F5/02
Inventor 匡春香王卓
Owner TONGJI UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com