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New intermediates for preparing ceritinib and preparation method of intermediate

A technology of ceritinib and intermediates, which is applied in the field of new intermediates and its preparation, can solve problems such as unfavorable drug needs and high product costs, and achieve the effects of reduced material costs, reduced production costs, and high purity

Active Publication Date: 2015-03-25
药源生物科技(启东)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the patent document WO2008073687A2, in the process of synthesizing intermediate 4, 40% (weight ratio) of expensive platinum dioxide is needed for catalysis, hydrogenation is 36 hours, and the yield is only 60%.
Among them, the cost of platinum dioxide catalyst accounts for more than half of the cost of raw materials for the preparation of ceritinib, resulting in very expensive final product costs, which is not conducive to meeting the drug needs of the general public

Method used

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  • New intermediates for preparing ceritinib and preparation method of intermediate
  • New intermediates for preparing ceritinib and preparation method of intermediate
  • New intermediates for preparing ceritinib and preparation method of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1. Preparation of 2-chloro-4-fluoro-5-nitro-toluene

[0024]

[0025] Put 135ml of concentrated sulfuric acid into the reaction flask, cool in an ice bath while stirring, and add 43.4g of fuming nitric acid dropwise. Continue to stir for 30 minutes after dropping to form mixed acid. At the same time, 315ml of concentrated sulfuric acid (3.5V) and 90.0g of 2-chloro-4-fluoro-toluene were put into another three-necked flask. Under ice-salt bath cooling, add the above-mentioned mixed acid composed of nitric acid and sulfuric acid into the sulfuric acid solution of 2-chloro-4-fluoro-toluene, and continue the reaction for 1-2 hours. While stirring, the reaction solution was slowly added to crushed ice to quench, and extracted twice with ethyl acetate. The ethyl acetate was combined, washed twice with water and once with saturated brine. The organic phase was concentrated to dryness to give 2-chloro-4-fluoro-5-nitro-toluene as an oil.

[0026] 1 H NMR (CDCl3...

Embodiment 2

[0027] Embodiment 2. Preparation of 2-chloro-4-isopropoxy-5-nitro-toluene

[0028]

[0029]2-Chloro-4-fluoro-5-nitro-toluene was dissolved in 1200ml of isopropanol and added to a 2L three-necked flask. Add 429 g of anhydrous potassium carbonate powder. Warm to reflux with stirring. The reaction was maintained at reflux for ~40 hours. Concentrate to remove most of the isopropanol. 2 L of water was added and extracted twice with ethyl acetate. The ethyl acetate layers were combined and washed with water. Concentration of ethyl acetate gave brown 2-chloro-4-isopropoxy-5-nitro-toluene.

[0030] 1 H NMR (CDCl3): δ7.71 (s, 1H), 7.07 (s, 1H), 4.61 (m, 1H), 2.34 (s, 3H), 1.40 (d, 3.2, 6H).

Embodiment 3

[0031] Example 3. Preparation of 4-(5-isopropoxy-2-methyl-4-nitro-phenyl)pyridine

[0032]

[0033] 78g of 2-chloro-4-isopropoxy-5-nitro-toluene, 42g of 4-pyridineboronic acid, 97g of potassium carbonate, 780mL of dioxane, 390mL of purified water, 7.67g of palladium acetate, and 35.85g of triphenylphosphine g was added to a 2L three-necked flask. Under nitrogen protection, the mixture was stirred and refluxed for 24 hours. Concentrate to remove most of the dioxane. 1.5 L of water was added, and extracted twice with ethyl acetate. The combined ethyl acetate was washed twice with saturated brine, and the organic phase was concentrated to dryness to obtain a brown solid 4-(5-isopropoxy-2-methyl-4-nitro-phenyl)pyridine, the compound 3.

[0034] 1 H NMR(CDCl3):δ8.72(m,2H),7.71(s,1H),7.31(m,2H),6.89(s,1H),4.63(m,1H),2.21(s,3H), 1.38(d,3.0,6H).

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Abstract

The invention relates to intermediates, namely a compound 1 of a formula (1) as shown in the specification and a compound 2 of a formula (2) as shown in the specification, for preparing ceritinib, or a chemically acceptable salt of the compound 2, wherein R represents the benzylic group of saturated or unsaturated aromatic ring methylene or heteroaromatic ring methylene, and X represents a halogen. The invention relates to a method for preparing a compound 4 by use of the new intermediates, namely the compound 1 and the compound 2, wherein the step of reduction from the compound 1 to the compound 2 is performed by use of a hydroboron or a composition thereof and an alcohol solvent; the compound 2 is reduced by use of a catalytic hydrogenation or transfer hydrogenation method to generate the compound 4. The route of preparing the compound 4 by use of the compound 1 and the compound 2 has the advantages that the chemical reduction step is combined with a catalytic hydrogenation, the use of expensive platinum dioxide is avoided and the cost of synthesizing the intermediate 4 of the ceritinib is effectively reduced.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a novel intermediate used for preparing a drug for treating lung cancer, ceritinib (LDK378), and a preparation method thereof. Background technique [0002] Lung cancer is one of the malignant tumors with the highest incidence rate in the world, and due to various factors such as the environment, its incidence rate is increasing at a rate of more than 3% per year. Among the diagnosed lung cancer patients, 80-85% are non-small cell lung cancer (NSCLC), and 2%-7% of the cases are driven by the rearrangement of the ALK gene, which leads to the accelerated growth of cancer cells. deterioration. Ceritinib is an oral, anaplastic lymphoma kinase (ALK) inhibitor that has made breakthrough progress in the treatment of patients with metastatic non-small cell lung cancer (NSCLC) in clinical research. On April 29, 2014, the U.S. Food and Drug Administration [FDA] approved ceritinib for t...

Claims

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Application Information

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IPC IPC(8): C07D213/30C07D211/70C07D211/26C07D401/12
CPCC07D211/26C07D211/70C07D213/30C07D401/12
Inventor 宋金峰唐文生何训贵王元
Owner 药源生物科技(启东)有限公司
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