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Method for preparing Ceritinib and intermediate compound of Ceritinib

A compound and oxidant technology, applied in the field of medicinal chemistry, can solve the problems of only 30-40% reaction yield, increased synthesis cost, complicated operation, etc., and achieves the effects of less organic solvent, improved synthesis efficiency and simple operation.

Inactive Publication Date: 2016-01-27
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The synthesis method of Ceritinib disclosed in the prior art includes complex reaction steps such as nitration and hydrogenation reduction, and almost every step of the reaction requires chromatographic column purification, the operation is complicated, the yield is low, and the synthesis cost increases accordingly
At the same time, when tert-butyl 4-(4-amino-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylate and 2,5-dichloro-N-(2-(iso When propylsulfonyl)phenyl)pyrimidin-4-amine condenses under microwave irradiation under the catalysis of palladium acetate, the reaction yield is only 30-40%

Method used

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  • Method for preparing Ceritinib and intermediate compound of Ceritinib
  • Method for preparing Ceritinib and intermediate compound of Ceritinib
  • Method for preparing Ceritinib and intermediate compound of Ceritinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0053] The preparation of embodiment 1a formula 4 compounds

[0054]

[0055] Formula 7 compound (50g, 0.299mol) is dissolved in acetonitrile (500mL), adds K 2 CO 3(49.5g), compound of formula 6 (57.4g, 0.313mol), heated at 60°C for 5h, added water (300ml) and ethyl acetate (1200ml) for extraction, separated the organic layer and concentrated to dryness to obtain 80g of compound product of formula 4, Yield 85%, HPLC: 99%.

[0056] 1 HNMR: 9.34(1H), 8.38(1H), 7.73-7.75(1H), 7.54-7.56(1H), 7.35-7.37(1H), 7.26-7.27(1H), 3.30-3.34(1H), 1.15-1.17 (6H).

Embodiment 1b

[0057] The preparation of embodiment 1b formula 4 compounds

[0058] Dissolve compound 7 (50g, 0.299mol) in ethanol (500mL), add Cs 2 CO 3 (70g), compound 6 (57.4g, 0.313mol), heated at 60°C for 5h, added water (200ml) and ethyl acetate (1000ml) for extraction, separated the organic layer and concentrated to dryness to obtain 77.2g of compound product of formula 4. Yield 82%, HPLC: 99%.

Embodiment 1c

[0059] The preparation of embodiment 1c formula 4 compounds

[0060] Dissolve compound of formula 7 (50g, 0.299mol) in acetone (200mL) and acetonitrile (300ml), add triethylamine (20ml), compound of formula 6 (57.4g, 0.313mol), heat at 60°C for 5h, add water (500ml) and ethyl acetate (1500ml) were extracted, the organic layer was separated and concentrated to dryness to obtain 80g of the compound product of formula 4, with a yield of 85%, HPLC: 99%.

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PUM

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Abstract

The invention provides a new intermediate compound for preparing Ceritinib and a preparation method for Ceritinib. The intermediate compound is shown as a formula 4 in the specification. The invention also discloses the preparation method for preparing the Ceritinib compound through the intermediate compound. The method possesses the advantages that operation is simple, yield is high, the prepared product is excellent in quality and the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a Ceritinib compound and a new intermediate compound thereof. Background technique [0002] Ceritinib (LDK378, also known as: Ceritinib) is an ALK inhibitor for the treatment of various types of advanced metastatic non-small cell lung cancer (NSCLC). Ceritinib is an anaplastic lymphoma enzyme (ALK) tyrosine kinase inhibitor developed for ALK+ patients who have previously received Crizotinib (crizotinib), the only approved drug prior to Ceritinib ALK kinase inhibitors. Structural formula is as shown in formula I: [0003] [0004] Ceritinib was developed by Novartis and was approved by the FDA on April 29, 2014. It is the second ALK inhibitor approved by the FDA. It is used as a specific drug for ALK-positive non-small cell lung cancer for crizotinib resistance or intolerance sufferers. In vitro tests have shown that its ALK inhibitory ...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D401/12
Inventor 赵俊宗在伟孙敏
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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