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Ceritinib intermediate and preparation method thereof

A technology of ceritinib and intermediates, applied in the field of drug synthesis, can solve problems such as operator injury and irritation, and achieve the effects of less side reactions, lower production costs, and high purity

Active Publication Date: 2018-01-19
SHANGHAI VASTPRO TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem solved by the present invention is to overcome that the raw material 2,4,5-trichloropyrimidine used in the preparation of ceritinib intermediate I in the prior art has a strong stimulating effect on eyes, respiratory tract and skin, and is easy to Cause harm to operators and other problems, thus provide a kind of ceritinib intermediate and preparation method thereof different from the prior art, the raw materials used in the preparation method of the present invention are safe and non-toxic, the reaction is simple and easy to operate, and the side reaction Less, use water for post-treatment or even crystallization, reduce production costs, and the obtained products have high purity and are easy to industrialize large-scale production

Method used

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  • Ceritinib intermediate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0056] Preparation of 2-methylthio-5-chloro-N-[2-[(1-methylethyl)sulfonyl]phenyl]-4-pyrimidinamine (Intermediate III)

[0057] In a dry three-necked flask, filled with nitrogen, added sodium hydride (1.5g, 0.0375mol) and DMSO (25mL), cooled to 0°C, and added dropwise 2-(isopropylsulfonyl)aniline (5g, 0.025mol) DMSO (12.5mL) solution (dropping rate is 1 / d / s), after the addition is complete, stir at 25°C for 1h, then add dropwise 4,5-dichloro-2-methylthiopyrimidine (5.4g, 0.028mol) DMSO (12.5 mL) solution (dropping rate: 1 / d / s), stirred at 25°C for 2 h, quenched with ice water (150 mL), precipitated solid, filtered, washed with water to obtain a yellow solid. The resulting solid was added with n-heptane (40 mL), stirred for 2 h, and filtered to obtain 7 g of a yellow solid with a yield of 78% and a purity of 99.2% by HPLC. ESMS m / z 358.0[M+H] +.1 H NMR (DMSO-D 6 ):δ9.66(s,1H),8.51(d,1H),8.46(s,1H),7.81-7.88(m,2H),7.41(t,1H),3.46-3.53(m,1H), 2.47(s,3H),1.16(d,6H).

Embodiment 2

[0059] Preparation of 2-methylthio-5-chloro-N-[2-[(1-methylethyl)sulfonyl]phenyl]-4-pyrimidinamine (Intermediate III)

[0060] In a dry three-necked flask, filled with nitrogen, added sodium hydride (1.5g, 0.0375mol) and DMF (25mL), cooled to 0°C, and added dropwise 2-(isopropylsulfonyl)aniline (5g, 0.025mol) DMF (12.5mL) solution (dropping rate is 1 / d / s), after the addition, stirred at 25°C for 1h, then added dropwise 4,5-dichloro-2-methylthiopyrimidine (5.4g, 0.028mol) DMF (12.5 mL) solution (dropping rate: 1 / d / s), stirred at 25°C for 2 h, quenched with ice water (150 mL), precipitated solid, filtered, and washed with water to obtain a yellow solid. The resulting solid was added with n-heptane (40 mL), stirred for 2 h, and filtered to obtain 7.4 g of a yellow solid with a yield of 82.4% and a HPLC purity of 99%.

Embodiment 3

[0062] Preparation of 2-methylthio-5-chloro-N-[2-[(1-methylethyl)sulfonyl]phenyl]-4-pyrimidinamine (Intermediate III)

[0063] In a dry three-necked flask, fill with nitrogen, add sodium hydride (1.3g, 0.0325mol) and acetonitrile (25mL), cool to 0°C, add dropwise 2-(isopropylsulfonyl)aniline (5g, 0.025mol) Acetonitrile (25mL) solution (dropping rate is 1 / d / s), after addition, stirred at 25°C for 1h, then added dropwise 4,5-dichloro-2-methylthiopyrimidine (9.6g, 0.05mol) Acetonitrile (25 mL) solution (dropping rate 1 / d / s), stirred at 25°C for 3 h, quenched with ice water (150 mL), precipitated solid, filtered, washed with water to obtain a yellow solid. The resulting solid was added with n-heptane (40 mL), stirred for 2 h, and filtered to obtain 6.8 g of a yellow solid, with a yield of 75.5% and a HPLC purity of 98.4%.

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Abstract

The invention discloses a ceritinib intermediate and a preparation method thereof. The preparation method of the ceritinib intermediate comprises the following steps: (1) under anhydrous oxygen-free conditions, in a polar aprotic solvent and under conditions of a metal hydride, performing a N-arylation reaction on an intermediate V and an intermediate IV to obtain an intermediate III; (2) in a solvent and under an acidic condition, hydrolyzing the intermediate III to obtain an intermediate II; and (3) in a solvent, performing a chlorination reaction on the intermediate II to obtain the ceritinib intermediate. The raw materials used in the preparation method provided by the invention are safe and non-toxic, reactions are simple and easy to operate, side reactions are few, water is adopted for post-treatment and even crystallization, thus production costs are reduced, the prepared product has high purity, and the ceritinib intermediate is easy for industrialized production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an intermediate of ceritinib and a preparation method thereof. Background technique [0002] Ceritinib (English name: Ceritinib; trade name: Zykadia TM ; CAS No.: 1032900-25-6) is an anticancer drug developed by Novartis Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) on April 29, 2014. Ceritinib is a capsule, an oral anaplastic lymphoma kinase (ALK) inhibitor (Anaplastic LymphomaKinase), used for advanced mesenchymal degeneration after treatment with crizotinib or intolerance Treatment of patients with Anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC). Its structure is shown in the following formula: [0003] [0004] The preparation method of ceritinib reported in the existing literature (see J.Med.Chem.2013,56,5676-5690) is as follows: [0005] [0006] Among them, 2,5-dichloro-N-[2-[(1-methylethyl)sulfo...

Claims

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Application Information

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IPC IPC(8): C07D239/47C07D239/42
Inventor 冯亚兵史科慧朱文峰
Owner SHANGHAI VASTPRO TECH DEV CO LTD
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