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Preparation method for micro-molecular kinase inhibitor

A catalyst, solvent-free technology, applied in the fields of organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of low total yield and environmental pollution, and achieve the effects of good economic benefits, high yield and short synthetic route

Active Publication Date: 2017-05-10
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Most of the currently reported documents use heavy metal palladium as a catalyst for the reaction, which seriously pollutes the environment and the overall yield is not high.

Method used

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  • Preparation method for micro-molecular kinase inhibitor
  • Preparation method for micro-molecular kinase inhibitor
  • Preparation method for micro-molecular kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] (1), preparation of compound (III)

[0068] Compound (II) (20g, 48.78mmol) and dimethyl malonate (6.44g, 48.78mmol) were dissolved in 1,4-dioxane (200ml), then potassium carbonate (13.48g, 97.56mmol) was added ), heated to 100° C. under stirring conditions, reacted for 6.5 h, and TLC detected that the reaction was complete. Spin off the solvent under reduced pressure, pour the residue into 200ml of water, extract three times with ethyl acetate (3x 100ml), combine the organic phases, then wash with water, brine, dry over anhydrous sodium sulfate, spin off the solvent, and use normal Slurry with heptane, filter with suction to obtain a filter cake, and dry to obtain a light gray solid, which is 19.4 g of compound (III), 86%.

[0069] 1 H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),5.31(s,1H),5.11( m,1H),3.73(s,6H),1.71(d,J=4.8Hz,3H).C 18 h 15 Cl 2 FN 2 o 7 Calcd: 460.0240, found: 460.0313.

[0070] (2), preparation of compound (IV)

[0071] ...

Embodiment 2

[0078] (1), preparation of compound (III)

[0079] Compound (II) (20g, 48.78mmol) and dimethyl malonate (6.77g, 51.22mmol) were dissolved in 1,4-dioxane (200ml), then potassium carbonate (13.48g, 97.56mmol) was added ), heated to 100° C. under stirring conditions, reacted for 6.5 h, and TLC detected that the reaction was complete. The solvent was spun off under reduced pressure, the residue was poured into 200ml of water, extracted three times with ethyl acetate (3x 200ml), the organic phases were combined, then washed with water, brine, dried over anhydrous sodium sulfate, and the solvent was spun off, and the obtained crude product was washed with normal Slurry with heptane, filter with suction to obtain a filter cake, and dry to obtain a light gray solid, which is 20.02 g of compound (III), 89%.

[0080] 1 H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),5.31(s,1H),5.11( m,1H),3.73(s,6H),1.71(d,J=4.8Hz,3H).C 18 h 15 Cl 2 FN 2 o 7 Calcd: 460.0240, f...

Embodiment 3

[0089] (1), preparation of compound (III)

[0090] Compound (II) (20g, 48.78mmol) and dimethyl malonate (6.77g, 51.22mmol) were dissolved in 1,4-dioxane (200ml), then potassium carbonate (13.48g, 97.56mmol) was added ), heated to 100° C. under stirring conditions, reacted for 6.5 h, and TLC detected that the reaction was complete. The solvent was spun off under reduced pressure, the residue was poured into 200ml of water, extracted three times with ethyl acetate (3x 200ml), the organic phases were combined, then washed with water, brine, dried over anhydrous sodium sulfate, and the solvent was spun off, and the obtained crude product was washed with normal Slurry with heptane, filter with suction to obtain a filter cake, and dry to obtain a light gray solid, which is 19.57 g of compound (III), 87%.

[0091] 1 H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),5.31(s,1H),5.11( m,1H),3.73(s,6H),1.71(d,J=4.8Hz,3H).C 18 h 15 Cl 2 FN 2 o 7 Calcd: 460.0240, f...

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Abstract

The invention relates to a preparation method for a micro-molecular kinase inhibitor. Specifically, the invention discloses a novel method for preparing the micro-molecular kinase inhibitor capable of treating locally-advanced or metastatic non-small cell lung cancer (NSCLC) with positive anaplastic lymphoma kinase (ALK). The method comprises the following steps: with a compound (II) as a starting material, carrying out a substitution reaction, a reduction reaction, an oxidation reaction, a cyclization reaction and a reduction and deprotection reaction so as to form crizotinib as shown in a formula (I) in the specification. The method provided by the invention has the advantages of environment-friendly synthetic route, simple and safe operation, high overall yield, good economic benefits, and facilitation industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a small molecule targeted drug 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy] for the treatment of non-small cell lung cancer - a preparation method of 5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-2-pyridinamine. Background technique [0002] Crizotinib is a small molecule kinase inhibitor for the treatment of anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). The English name is Crizotinib, and the chemical name is 3 -[(1R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl] -2-Pyridinamine, trade name XALKORI (trade name in Chinese) was successfully developed by Pfizer, and was approved for marketing by the US FDA in 2011, and then marketed in Japan and the European Union, and was approved for marketing by the Chinese SFDA in 2013 . Crizotinib targets ALK, hepatocyte growth factor recep...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/00
CPCC07D401/14
Inventor 刘海李函璞李健之池王胄郑肖利孙黎
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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