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Pyridine derivatives and preparation methods thereof

A derivative, pyridine technology, applied in the field of pyridine derivatives and its preparation, can solve the problems of many by-products, high cost, cumbersome operation, etc., and achieve the effect of less by-products, simple operation, and low cost

Inactive Publication Date: 2013-12-04
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The technical problem to be solved by the present invention is that in order to overcome the defects of low reaction yield, cumbersome operation, high cost, many by-products and unfavorable industrial production in the existing method for preparing crizotinib, pyridine Derivatives and methods for their preparation

Method used

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  • Pyridine derivatives and preparation methods thereof
  • Pyridine derivatives and preparation methods thereof
  • Pyridine derivatives and preparation methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Tert-butyl-4-(4-(6-(bis(tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine Preparation of -3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1)

[0037]Add compound 2 (racemate) (2.10g, 3.35mmol) in 20mlDMF, then add compound 3 (1.33g, 4.02mmol), sodium carbonate aqueous solution (3.0 molar equivalent of compound 2), nitrogen replacement 5 times, add 0.13gPd(PPh 3 ) 3 Cl 2 , replaced with nitrogen 5 times, heated to 80-90°C, then reacted and stirred for 8h, cooled the reaction to room temperature, diluted with ethyl acetate, filtered with diatomaceous earth, washed with ethyl acetate, and the filtrate was washed with water and saturated brine in turn, anhydrous It was dried over sodium sulfate, concentrated, and 1.5 g of light yellow solid was obtained by column chromatography (petroleum ether / ethyl acetate=0-100% gradient elution). Yield: 60%. ee=0%. m / z (MH + )750, 1 H-NMR (400MHz, CDCl3) δ1.27-1.43 (S, 18H), δ1.47-1.55S, 9H) ...

Embodiment 2

[0038] Example 2 (tert-butyl-4-(4-(6-(bis(tert-butoxycarbonyl)amino)-5-(1R-(2,6-dichloro-3-fluorophenyl)ethoxy) Pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate)

[0039] Add compound 2 (2.10g, 3.35mmol) of R type in 20mlDMF, then add compound 3 (1.33g, 4.02mmol), sodium carbonate aqueous solution (3.0 molar equivalent of compound 2), nitrogen replacement 5 times, add 0.13gPd (PPh 3 ) 3 Cl 2 , replaced with nitrogen 5 times, heated to 80-90°C, then reacted and stirred for 8h, cooled the reaction to room temperature, diluted with ethyl acetate, filtered with diatomaceous earth, washed with ethyl acetate, and the filtrate was washed with water and saturated brine in turn, anhydrous It was dried over sodium sulfate, concentrated, and subjected to flash column chromatography (petroleum ether / ethyl acetate=0-100% gradient elution) to obtain 1.6 g of light yellow solid. Yield: 64%. ee = 99.4%. m / z (MH + )750, 1 H-NMR (400MHz, CDCl3) δ1.27-1.43 (S, 18H), δ1.47-1.55S, 9H...

Embodiment 3

[0040] Example 3 (tert-butyl-4-(4-(6-(bis(tert-butoxycarbonyl)amino)-5-(1S-(2,6-dichloro-3-fluorophenyl)ethoxy) Pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate)

[0041] Add compound 2 (2.10g, 3.35mmol) of S type in 20mlDMF, then add compound 3 (1.33g, 4.02mmol)), sodium carbonate aqueous solution (3.0 molar equivalent of compound 2), nitrogen replacement 5 times, add 0.13 gPd(PPh 3 ) 3 Cl 2 , replaced with nitrogen 5 times, heated to 80-90°C, then reacted and stirred for 8h, cooled the reaction to room temperature, diluted with ethyl acetate, filtered with diatomaceous earth, washed with ethyl acetate, and the filtrate was washed with water and saturated brine in turn, anhydrous It was dried over sodium sulfate, concentrated, and subjected to flash column chromatography (petroleum ether / ethyl acetate=0-100% gradient elution) to obtain 1.6 g of light yellow solid. Yield: 64%. ee > 99%. m / z (MH + )750, 1 H-NMR (400MHz, CDCl3) δ1.27-1.43 (S, 18H), δ1.47-1.55S, 9H)...

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Abstract

The invention discloses a pyridine derivative 1, wherein carbon marked with * is chiral carbon. The invention also discloses a preparation method of the pyridine derivative 1. The preparation method of the pyridine derivative 1 comprises the following step: in a solvent, under the protection of an inert gas, under the effects of a base and a catalyst, a Suzuki reaction of a compound 2 and a compound 3 is performed to obtain the compound 1. The invention also discloses a preparation method of a pyridine derivative 4, and the preparation method of the pyridine derivative 4 comprises the following steps: 1) preparing the compound 1 by the preparation method of the pyridine derivative 1; and 2) reacting the compound 1 prepared by the step 1) with an agent for removing a t-butyloxycarboryl protection group to perform a reaction for removing the t-butyloxycarboryl protection group. The preparation methods of the invention have the advantages of high yield, simple operation, low cost, and few by-products, and are suitable for industrial production.

Description

technical field [0001] The present invention relates to a novel pharmaceutical intermediate and a preparation method thereof, in particular to a pyridine derivative and a preparation method thereof. Background technique [0002] C-met is a receptor tyrosine kinase, encoded by the Met proto-oncogene, and transduces the biological effects of hepatocyte growth factor (HGF), also known as expander factor (SF). C-met and HGF are expressed in many tissues, although their expression is usually mainly restricted to cells of epithelial and mesenchymal origin, respectively. C-met and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenetic differentiation, and the formation of 3-microtubule-like structures, and HGF / SF is a vascular Generating factor, and c-met signaling in endothelial cells can induce many cellular responses (proliferation, metastasis, invasion) necessary for angiogenesis. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCY02P20/55
Inventor 魏哲鹏陈纪袁哲东张华
Owner SHANGHAI INST OF PHARMA IND CO LTD
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