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Preparation method of tyrosine kinase inhibitor

A technology of hydrochloric acid and inert solvent, applied in the field of pharmaceutical synthesis, can solve the problems of low yield and difficult purification, and achieve the effects of good reproducibility, avoiding many by-products and simple operation.

Inactive Publication Date: 2016-04-06
芷威(上海)化学科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In summary, with reference to existing patents and literature, the biggest difficulty of the current rociletinib synthesis method is almost all concentrated in the synthesis of the intermediate 5, N-(3-nitrophenyl)-2-chloro-5-trifluoromethyl Based pyrimidin-4-amine, the ratio of the target intermediate to its by-product isomer is almost 1:1, its purification is difficult, the yield is low, and it has not been effectively solved for a long time, which has brought many problems to pharmaceutical developers , therefore, it is urgent to develop a new synthetic route to solve the above problems

Method used

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  • Preparation method of tyrosine kinase inhibitor
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  • Preparation method of tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of Example 1 Compound (Ⅳ) 2-methoxy-4-(4-acetyl-1-piperazinyl)nitrobenzene

[0026] Add 140g (0.82mol) of compound (II) 2-methoxy-4-fluoronitrobenzene to a dry 500mL three-necked flask, then add 150mL of 1,4-dioxane and compound (III) acetylpiperazine 500g (3.90mol), heat to reflux for 2~3h (100°C), monitor the reaction by TLC until the raw material disappears, concentrate the reaction system after cooling down, and add 250mL of water when most of the dioxane is evaporated, and stir for about 0.5h , suction filtration, the filter cake was rinsed with 200mL of water to obtain a yellow solid, and dried at 50-60°C to obtain 217.56g of the product, with a yield of 95%.

[0027] 1 HNMR: (d 6 -DMSO), δ: 2.12(s, 3H); 3.61(m, 4H); 3.66(m, 4H); 3.95(s, 3H); 6.59(s, 1H); 6.64(d, 1H); 7.99( d, 1H).

Embodiment 2

[0028] The preparation of embodiment 2 compound (Ⅴ) 2-methoxy-4-(4-acetyl-1-piperazinyl) aniline

[0029] Add 33g (0.11mol) of compound (Ⅳ), 10%Pd / C1.5g, and 150mL of anhydrous methanol to a dry 500mL reaction flask, stir, and replace with nitrogen for 3 times, then inject hydrogen at normal pressure and stir, and react at room temperature for 4h Afterwards, TLC monitored the completion of the reaction, and the system was filtered and concentrated to obtain 24.68 g of the product, with a yield of 90%.

[0030] 1 HNMR: (d 6 -DMSO), δ: 2.02(s, 3H); 2.85~2.94.61(m, 4H); 3.52~3.56(m, 4H); 3.74(s, 3H); 4.28(b, 2H); 6.29(d , 1H); 6.52-6.54 (d, 2H).

Embodiment 3

[0031] Example 3 Compound (VII) 2-[[4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-4-chloro-5-(trifluoromethyl)pyrimidine preparation of

[0032] (1) Under the protection of nitrogen, add 94.06g (0.69mol) of zinc chloride and 350ml of anhydrous tetrahydrofuran, control the temperature at 15-20°C, and slowly add compound (Ⅵ) 2,4-dichloro-5-trifluoromethyl A mixture of 49.90 g (0.23 mol) of pyridine and 150 mL of tetrahydrofuran. Maintain this temperature for 1 hour;

[0033] (2) Compound （Ⅴ） Dissolve 47.8g (0.19mol) in 120mL anhydrous tetrahydrofuran, add dropwise to the above preparation solution, stir for 30min, add 116.37g (1.15mol) triethylamine dropwise, react at room temperature for 20-24h after addition, monitor the reaction by TLC Complete, extracted 3 times with 100mL dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated, and crystallized with acetonitrile:acetone=3:1 to obtain 84.03 g of pink to light yell...

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Abstract

The invention relates to a novel preparation method of a tyrosine kinase inhibitor RociletinibN-[3-[[2-[[4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)-4-pyrimidyl]amino]phenyl]-2-acrylamide. A chemical compound (VII)2-[[4-(4--acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-4-chloro-5-(trifluoromethyl)pyrimidine is innovatively used as a key intermediate for synthesis of Rociletinib, the proportion of a target product in a reaction system to isomer byproducts can be higher than 4:1, relatively higher selectivity is realized, and the defects that multiple byproducts are produced and refining and purifying are difficult in an existing synthesis method are overcome. The preparation method is simple to operate, good in reproducibility, economical, environment-friendly and suitable for industrial production, high-purity Rociletinib can be prepared, and the total yield reaches 60%-65%.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a tyrosine kinase inhibitor - New preparation method of rociletinib. Background technique [0002] Rociletinib (CO-1686, N-[3-[[2-[[4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-5-(trifluoromethyl )-4-pyrimidinyl]amino]phenyl]-2-acrylamide, see compound 1 in Reaction Formula 1) is the third-generation tyrosine kinase inhibitor of Clovis Oncology, mainly targeting non-small cell lung cancer with T790M mutation ( NSCLC) is an irreversible epidermal growth factor receptor (EGFR) inhibitor. Studies have shown that Rociletinib is an oral and highly effective tyrosine kinase inhibitor, which can inhibit protein kinase activity through an irreversible covalent bond with Cys797 at the ATP-binding pocket of the EGFR tyrosine kinase region. More importantly, Rociletinib can selectively inhibit EGFR activating mutations (such as L858R) and acquired drug resistance mutations (s...

Claims

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Application Information

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IPC IPC(8): C07D239/48
CPCC07D239/48
Inventor 付开勇李华张长江
Owner 芷威(上海)化学科技有限公司