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Method for preparing antitumor drug ceritinib intermediate

An anti-tumor drug, ceritinib technology, applied in the field of medicinal chemistry, can solve the problems of difficult recovery of precious metal Pd and organic ligands, high production cost, and achieve the effect of reducing catalytic cost, improving efficiency and good repeatability

Inactive Publication Date: 2018-12-18
刘耿熙
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In CN 104892526 A, under alkaline conditions (sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, potassium carbonate, cesium carbonate, etc.), palladium acetate, palladium chloride and other palladium salts and phosphorus-containing ligands are used to form catalysts to catalyze reaction, achieved a yield of 85%-90%, but the noble metal Pd and organic ligands in this system are difficult to recover, resulting in higher production costs

Method used

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  • Method for preparing antitumor drug ceritinib intermediate
  • Method for preparing antitumor drug ceritinib intermediate
  • Method for preparing antitumor drug ceritinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] In order to remove noble metal Pd and phosphorus-containing ligands, the present invention screens metal salts through high-throughput, in order to obtain a simple catalytic system. The present invention screens the following catalysts:

[0031] Add 2-(isopropylsulfonyl)aniline (1.99g, 10mmol), 2,4,5-trichloropyrimidine (2.75g, 15mmol, 1.5eq), DMSO 36ml, potassium tert-butoxide (1.68 g, 15mmol, 1.5eq), metal salt (2mmol, 0.2eq) were reacted at 80-90°C, and the reaction solution was taken every 2h for HPLC analysis, and the 2-(isopropylsulfonyl group in the reaction solution was sampled twice before and after ) When the aniline concentration no longer changes, it is considered as the end of the reaction by default, and the catalytic effects of each metal salt are shown in Table 1:

[0032] The screening of table 1 metal salt catalyst

[0033]

[0034]

[0035] Note: The peak area of ​​2,4,5-trichloropyrimidine is not counted when the area normalization method is u...

Embodiment 2

[0038] When zinc acetate was determined to be the catalyst, the present invention further optimized the solvent type and reaction temperature, and added 2-(isopropylsulfonyl)aniline (1.99g, 10mmol), 2,4,5-tris Chloropyrimidine (2.75g, 15mmol, 1.5eq), solvent 36ml, potassium tert-butoxide (1.68g, 15mmol, 1.5eq), zinc acetate (2mmol, 0.2eq) were reacted at different temperatures, and the reaction solution was taken every 2h Carry out HPLC analysis, when 2-(isopropylsulfonyl) aniline concentration no longer changes in the two sampling reaction solutions before and after, acquiesce as reaction finishes, count the reaction situation of each reaction system, the result is as shown in table 2:

[0039] Table 2 The optimization of solvent type and reaction temperature

[0040]

[0041]

[0042] The above results show that the use of N-methylpyrrolidone (NMP) and PEG400 as a solvent has achieved a good reaction conversion rate, but due to the high viscosity of PEG400, NMP is sele...

Embodiment 3

[0044]When establishing zinc acetate as a catalyst, NMP as a solvent, and a reaction temperature of 120°C, the molar amount of the present invention to the type of alkali, 2,4,5-trichloropyrimidine (in terms of 2-(isopropylsulfonyl)aniline moles) amount as the benchmark), the catalyst dosage (based on the molar amount of 2-(isopropylsulfonyl) aniline) has been further optimized;

[0045] Add 2-(isopropylsulfonyl)aniline (1.99g, 10mmol), 2,4,5-trichloropyrimidine (11-20mmol, 1.1-2.0eq), NMP 36ml, base (15mmol, 1.5 eq), zinc acetate (0.5-5mmol, 0.05-0.5eq) were reacted at 120°C, and the reaction solution was taken every 2 hours for HPLC analysis, and the concentration of 2-(isopropylsulfonyl)aniline in the reaction solution was sampled twice before and after When it does not change, it is considered as the end of the reaction by default, and the reaction conditions of each reaction system are counted, and the results are shown in Table 3:

[0046] Table 3 The influence of catal...

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Abstract

The invention belongs to the technical field of medical chemistry, and concretely relates to a method for preparing an antitumor drug ceritinib intermediate. The method utilizes zinc salt as a catalyst under strong alkali conditions to catalyze the production of 2,5-dichloro-N-[2(isopropylsulfonyl)phenyl]pyrimidine-4-amine by using 2-(isopropylsulfonyl)aniline and 2,4,5-trichloropyrimidine as rawmaterials. The method of the invention overcomes the disadvantages of using the noble metal Pd in the prior art, does not need to use an expensive phosphorus-containing ligand, has the advantages of mild reaction conditions and high yield, and has industrial application prospects.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for preparing an antitumor drug ceritinib intermediate. Background technique [0002] Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) receptor inhibitor developed by Novartis, Switzerland. Treatment of patients with resistant advanced ALK-positive metastatic non-small cell lung cancer (NSCLC). Ceritinib was approved for marketing by the US FDA on April 29, 2014, with the trade name Zykadia; it was approved for marketing by EMEA in Europe on May 6, 2015, and it was launched in Japan on March 28, 2016, and on May 26, 2017 , FDA approved for the first-line treatment of ALK mutation-positive metastatic non-small cell lung cancer (NSCLC). [0003] The chemical name of ceritinib is 5-chloro-N4-[(2-isopropylsulfonyl)phenyl]-N2-[2-isopropoxy-5-methyl-4-(piperidine-4- Base) phenyl]-2,4-pyrimidinediamine, the molecular weight is 558.14,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 刘耿熙陈兰华季辉李靖梁利
Owner 刘耿熙
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