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Preparation method of tucatinib

A technology of tucatinib and hydroxyl, which is applied in the field of preparation of tucatinib, can solve problems such as product purity and yield impact, failure to meet environmental protection requirements, abnormal odor, etc., achieve simple and environmentally friendly routes, reduce operation difficulty and Environmental requirements, high yield effect

Active Publication Date: 2021-01-01
SHANDONG HUIHAI PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The total yield of this route has been significantly improved, and the product purification steps and purity have also met the requirements of API, but the route involves malodorous sulfide intermediates, expensive palladium carbon catalysts and toxic methylation Reagent methyl trifluoromethanesulfonate, the last step requires high-temperature reaction, which has an impact on product purity and yield, and this step reaction also produces odorous methyl mercaptan, which cannot meet the environmental protection requirements of industrial production

Method used

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  • Preparation method of tucatinib
  • Preparation method of tucatinib
  • Preparation method of tucatinib

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Under nitrogen protection, dissolve 0.1mol of 4-hydroxy-6-chloroquinazoline into 200ml of N,N-dimethylformamide, add 0.003mol of cuprous bromide, 0.11mol of potassium phosphate, and 0.006mol of N-methylnicotinamide , 0.15 mol of 2-amino-4,4-dimethyl-4,5-dihydrooxazole, and then the reaction solution was heated to 120° C. for 20 hours. Cool, concentrate under reduced pressure to remove the solvent, add 200ml of dichloromethane and saturated aqueous ammonium chloride solution, separate the layers, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and recrystallize the residue with methanol and water to obtain a white solid product with a yield of 82.1%.

[0030] 4-Hydroxy-6-(4,4-dimethyl-4,5-dihydrooxazol-2-amino)quinazoline 0.05mol and Carter condensing agent BOP0.06mol were dissolved in 200ml of acetonitrile, added N, N-dimethylaminopyridine 0.075mol, stirred at room temperature for 0.5 hours, then a...

Embodiment 2

[0032]Under nitrogen protection, 0.1 mol of 4-hydroxy-6-chloroquinazoline was dissolved in 200 ml of ethylene glycol monomethyl ether, and 0.001 mol of cuprous bromide, 0.14 mol of potassium phosphate, 0.004 mol of N-methylbenzamide, 0.18 mol of 2-amino-4,4-dimethyl-4,5-dihydrooxazole, and then the reaction solution was heated to 100° C. for 25 hours. Cool, concentrate under reduced pressure to remove the solvent, add 200ml of dichloromethane and saturated aqueous ammonium chloride solution, separate the layers, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and recrystallize the residue with methanol and water to obtain a white solid product with a yield of 86.2%.

[0033] 4-Hydroxy-6-(4,4-dimethyl-4,5-dihydrooxazol-2-amino)quinazoline 0.05mol and Carter condensing agent BOP0.075mol were dissolved in 200ml tetrahydrofuran, and diiso Propylethylamine 0.06mol, stirred at 40°C for 0.7 hours, then added 4-(...

Embodiment 3

[0035] Under nitrogen protection, 0.1 mol of 4-hydroxy-6-chloroquinazoline was dissolved in 200 ml of a mixed solvent of dimethyl sulfoxide and ethylene glycol, and 0.005 mol of cuprous bromide, 0.1 mol of potassium phosphate, and N-methyl Nicotinamide 0.002mol, 2-amino-4,4-dimethyl-4,5-dihydrooxazole 0.1mol, and then the reaction solution was heated to 150°C for 10 hours. Cool, concentrate under reduced pressure to remove the solvent, add 200ml of dichloromethane and saturated aqueous ammonium chloride solution, separate the layers, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and recrystallize the residue with methanol and water to obtain a white solid product with a yield of 84.7%.

[0036] Dissolve 0.05mol of 4-hydroxy-6-(4,4-dimethyl-4,5-dihydrooxazol-2-amino)quinazoline and 0.1mol of Carter’s condensing agent BOP into 200ml of ethylene glycol dimethyl ether Add 0.1 mol of triethylamine, stir the ...

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Abstract

The invention relates to a preparation method of tucatinib. The method comprises the following steps: by taking 4-hydroxy-6-chloroquinazoline as a raw material, firstly carrying out copper-catalyzed C-N cross-coupling reaction on the 4-hydroxy-6-chloroquinazoline and 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole, then activating the 4-hydroxy of quinazolinone by adopting a BOP, and enabling product and 4-([1, 2, 4] triazolo [1, 5-a] pyridine-7-yloxy)-3-methylaniline to be subjected to a nucleophilic substitution reaction to obtain tucatinib. With the method, using of high-corrosivity and high-toxicity reagents is avoided, and the method has low requirements on equipment, the operation difficulty and environmental protection requirements are reduced, and the method has the advantages of high product yield and high product purity; the process is simple and environment-friendly and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of tucatinib. Background technique [0002] Tucatinib (Tucatinib; Tucatinib; Irbinitinib, ARRY-380, ONT-380) is a small-molecule oral tyrosine kinase (TKI) inhibitor that has Highly specific target selectivity. On April 17, 2020, the U.S. FDA approved tucatinib in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adults with previously treated advanced HER2-positive breast cancer that cannot be surgically removed or metastasized patient. Tucatinib was originally developed by Array Biopharma, and after being transferred to Oncothyreon (ONTY) (later renamed Cascadian Therapeutics), it was acquired by Seattle Genetics Inc. and launched on the market. Tucatinib has good blood-brain barrier permeability, which is of great significance to the treatment of HER2-positive breast cancer brain metastases. A...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 张海钟强刘志威方志康张永霞王明飞王磊
Owner SHANDONG HUIHAI PHARMA & CHEM
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