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New synthesis technology of ceritinib intermediate

A technology for ceritinib and intermediates, which is applied in the field of new preparation of ceritinib intermediate 4--piperidine-1-carboxylate tert-butyl ester, which can solve the problem of increased manufacturing costs, high dosage, and difficulty in industrialization and other problems, to achieve the effect of short steps, low cost of raw materials, and simple operation

Inactive Publication Date: 2016-04-06
SHANGHAI STEPPHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This synthesis method has the following disadvantages: the first step of the reaction needs to be carried out under microwave conditions, and it is difficult to realize large-scale production; secondly, the reaction needs to use expensive palladium catalysts and phosphine-containing ligands, which cannot be recycled, which increases the manufacturing cost
The second-step hydrogenation reaction requires the use of expensive platinum oxide, the amount of which is as high as 0.4 equivalent of the reactant; the solvent uses a mixed solvent of trifluoroacetic acid and acetic acid, which puts forward high requirements on the material of the enlarged reactor; in addition , the reaction product of each step needs to be purified by column chromatography, which is not suitable for scale-up production
This method has the following shortcomings: the preparation of boric acid and triflate derivatives is inconvenient, and harsh conditions such as anhydrous and oxygen-free, low temperature are required, and it is difficult to realize industrialization and reduce costs

Method used

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  • New synthesis technology of ceritinib intermediate
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  • New synthesis technology of ceritinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Preparation of tert-butyl 4-(5-isopropyl-2-methyl-4-nitrobenzene)-3,6-dihydropiperidine-1-carboxylate

[0021] 1-Chloro-5-isopropyl-2-methyl-4-nitrobenzene (25.3g, 0.11mol), N-tert-butoxy-1,2,5,6-tetrahydropyridine-4-boronic acid Pinacol ester (30.9g, 0.1mol), potassium carbonate (13.8g, 0.1mol), tetrakistriphenylphosphine palladium (1.15g, 0.001mol, 1% eq.) were added to toluene / water (220mL / 220mL) in sequence In the reaction mixture, the reaction mixture was stirred at 70-80 degrees Celsius for 5 hours (under nitrogen protection), TLC showed that the reaction was complete, the reaction mixture was cooled to 20-30 degrees Celsius, suction filtered, and n-heptane (220 mL) was added to the filtrate , layered, after the organic layer was concentrated to dry solvent, n-heptane (220mL) was added to the residue, stirred at 0-10 degrees Celsius for 2 hours, filtered with suction, and the filter cake was vacuum-dried at 40-50 degrees Celsius to obtain off-white powder tert-bu...

Embodiment 2

[0023] Preparation of tert-butyl 4-(5-isopropyl-2-methyl-4-nitrobenzene)-3,6-dihydropiperidine-1-carboxylate

[0024] 1-Chloro-5-isopropyl-2-methyl-4-nitrobenzene (25.3g, 0.11mol), N-tert-butoxy-1,2,5,6-tetrahydropyridine-4-boronic acid Pinacol ester (30.9g, 0.1mol), potassium phosphate (21.2g, 0.33mol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58.48g, 0.08mol , 0.8eq.) were sequentially added to the 1,4-dioxane / water (220mL / 220mL) reaction mixture, the reaction mixture was stirred at 90-101 degrees Celsius for 4 hours (under nitrogen protection), TLC showed that the reaction was complete, and the reaction mixture Cool the liquid to 20-30 degrees Celsius, filter with suction, add n-heptane (220mL) to the filtrate, and separate the layers. After the organic layer is concentrated to dryness, add n-heptane (220mL) to the residue, Stir for 2 hours, filter with suction, and vacuum-dry the filter cake at 40-50 degrees Celsius to obtain off-white powder 4-(5-isopr...

Embodiment 3

[0026] Preparation of tert-butyl 4-(5-isopropyl-2-methyl-4-nitrobenzene)-3,6-dihydropiperidine-1-carboxylate

[0027] 1-Chloro-5-isopropyl-2-methyl-4-nitrobenzene (25.3g, 0.11mol), N-tert-butoxy-1,2,5,6-tetrahydropyridine-4-boronic acid Pinacol ester (30.9g, 0.1mol), potassium carbonate (13.8g, 0.10mol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.22g, 0.0003mol , 0.3% eq.) was added to N,N-dimethylformamide / water (220mL / 220mL) reaction mixture in sequence, and the reaction mixture was stirred at 90-101 degrees Celsius for 4 hours (under nitrogen protection), and TLC showed that the reaction was complete , the reaction mixture was cooled to 20-30 degrees Celsius, suction filtered, and n-heptane (220mL) was added to the filtrate, and the layers were separated. After the organic layer was concentrated to dry solvent, n-heptane (220mL) was added to the residue, Stir at -10°C for 2 hours, filter with suction, and dry the filter cake in vacuum at 40-50°C to obtai...

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Abstract

The purpose of the invention is to provide a new synthesis technology of a ceritinib intermediate. The technology is characterized in that the ceritinib intermediate tert-butyl 4-(4-amino-5-isopropyl-2-methylphenyl)-piperidyl-1-carboxylate is prepared through a Suzuki coupling and hydrogenation reaction of 1-chloro-5-isopropyl-2-methyl-4-nitrobenzene and N-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridinyl-4-boronic acid pinacol ester. The technology has the advantages of short steps, simple operation, low raw material cost, and suitableness for amplified production.

Description

technical field [0001] The invention relates to a novel preparation method of ceritinib intermediate 4-(4-amino-5-isopropyl-2-methylphenyl)-piperidine-1-carboxylic acid tert-butyl ester. technical background [0002] Ceritinib is an anticancer drug approved by the FDA on April 29, 2014. Its trade name is Zykadia, developed by Novartis Pharmaceuticals. Zykadia is an oral, selective anaplastic lymphoma kinase (ALK) inhibitor. In the clinical treatment of lung cancer, ALK is an important therapeutic target. The ALK gene can fuse with other genes to express an abnormal fusion protein that promotes the formation and growth of cancer cells. The FDA granted Breakthrough Therapy Designation to Zykadia in March 2013. [0003] Disclosed in the literature (J.Med.Chem., 2013,56,5675-5690), ceritinib is obtained by reacting compounds A and B in isopropanol, and compound A is obtained from the intermediate 4-(4-amino-5 -Isopropyl-2-methylphenyl)-piperidine-1-carboxylic acid tert-butyl ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/26
Inventor 田勇曾旭辉唐飞宇廖文胜
Owner SHANGHAI STEPPHARM CO LTD
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