Preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine

A technology of propylsulfonyl and benzenesulfonyl, which is applied in the field of preparation of ceritinib to achieve the effects of reduced production cost, stable quality and high purity

Inactive Publication Date: 2015-09-09
2Y CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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  • Preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine
  • Preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine
  • Preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine

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Experimental program
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Effect test

Embodiment 1

[0042] Embodiment one 2-(isopropyl mercapto) aniline

[0043]

[0044] Add o-aminothiophenol (99.00g) and water (300mL) into the reaction flask, and stir. NaOH aqueous solution. 116.85 g of 2-bromopropane was added dropwise. After the dropwise addition, the temperature was raised to 40-50° C. for 2 hours to react. After the reaction was completed, it was cooled, and ethyl acetate was added to extract twice. The organic phases were combined and washed once with water. The solvent was distilled off to obtain 125.6 g of 2-(isopropylmercapto)aniline. Yield 95%.

[0045] MS (ESI+): 168.1 (M+1)+.

Embodiment 2

[0046] Example two N-(2-(isopropylthio)phenyl)acetamide

[0047]

[0048] 2-(Isopropylmercapto)aniline (132g), acetic acid (132mL) were added into the reaction flask. Stir and heat up to 40°C. Acetic anhydride (96.80 g) was added dropwise. Stir for 30 minutes after the dropwise addition is complete. After the reaction was completed, it was poured into ice water and extracted twice with ethyl acetate. The organic phases were combined and washed once with water. The solvent was distilled off to obtain 161.9 g of N-(2-(isopropylthio)phenyl)acetamide. Yield 98%.

[0049] MS(ESI+):210.1(M+1)+. 1H NMR(CDCl3):δ8.40(d,4.0,1H),7.47-7.49(m,1H),7.30-7.34(m,1H),7.00-7.04(m,1H),3.09-3.14(m, 1H), 2.21(s, 3H), 1.28-1.32(d, 2.6, 6H).

Embodiment 3

[0050] Example three N-(2-(isopropylsulfonyl)phenyl)acetamide

[0051]

[0052] N-(2-(isopropylthio)phenyl)acetamide (165 g), acetic acid (330 mL) were added to the reaction flask. Stir and heat up to 40°C. Sodium perborate tetrahydrate (364 g) was added in portions. Stirring was continued at 40°C for 2 hours after the addition was complete. Raise the temperature to 50-60°C and continue the reaction until the reaction is complete. Cool to 20-30°C. Add to ice water. Suction filtration, the filter cake was washed twice with water. Collect the filter cake. After drying, 173 g of N-(2-(isopropylsulfonyl)phenyl)acetamide was obtained as a tan solid. Yield 91%

[0053] MS (ESI+): 242.1 (M+1)+. 1H NMR(CDCl3):δ8.46-8.50(m,1H),7.79-7.83(m,1H),7.59-7.65(m,1H),7.20-7.25(m,1H),3.16-3.22(m, 1H), 1.28-1.32 (m, 6H).

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Abstract

The invention relates to a novel preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine. According to the method, o-aminothiophenol is taken as the starting raw material, and 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine is obtained after 5 steps including alkylation, acylation, oxidation, hydrolysis and coupling. Compared with the conventional processes, the process does not use a stinking isopropyl mercaptan reagent and is more environment-friendly. Raw materials for the whole synthesis route are easy to get, the operation of a reaction unit is simple and convenient, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine and its use in the preparation of ceritinib. Background technique [0002] Lung cancer is the malignant tumor with the highest incidence rate in the world, and due to various factors such as the environment, it is increasing at a rate of more than 3% per year. Among the diagnosed patients, 80-85% are non-small cell lung cancer (NSCLC), and 2%-7% of the cases are driven by rearrangement of anaplastic lymphoma kinase (ALK), which leads to cancer cells Accelerated growth and disease progression. Ceritinib is an oral, selective ALK inhibitor, which has made a breakthrough 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 the treatment of anaplastic lymphoma kinase-positive (ALK+) metastatic disease that has pr...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07C323/41C07C317/40C07D401/12
CPCC07D239/42C07C317/40C07C323/41C07D401/12
Inventor 王元宋金峰唐文生何训贵
Owner 2Y CHEM
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