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Synthesis method of Tucatinib and intermediate product thereof

A synthesis method and compound technology, applied in the field of synthesis of tucatinib and its intermediate products, can solve problems such as expensive, difficult, and scaled-up production

Pending Publication Date: 2020-10-27
宁波药腾医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is tedious, the total yield is only 5.7%, and the expensive catalyst Pd2dba3 and lithium hexamethyldisilazide LiHDMS, which is not suitable for industrial production, are needed in the synthetic route. It is difficult to scale up production and is not suitable for industrial production.

Method used

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  • Synthesis method of Tucatinib and intermediate product thereof
  • Synthesis method of Tucatinib and intermediate product thereof
  • Synthesis method of Tucatinib and intermediate product thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Embodiment 1: the synthetic route of the hydrochloride of compound as shown in VI

[0079] First, in a 500 mL flask, the compound represented by formula II (10.00 g, 81.23 mmol) and sodium bromide (420 mg, 0.05 eq) were added, and thionyl chloride (45 mL) was added dropwise. The resulting mixture was slowly heated to reflux, during which time a vigorous evolution of sulfur dioxide occurred. After 16 h at reflux, the solution was cooled to room temperature, diluted with toluene (50 mL), and concentrated in vacuo. This process is repeated twice. Then ammonia water (20 vol, 180 mL) was slowly added dropwise to the obtained yellow crude product at 0°C. Stir at room temperature for 18 h, ice-bath, precipitate a white solid, then filter the suspension to obtain a crude light white filter cake, wash with water to obtain a pure product. The filter cake was vacuum dried to obtain 10.8 g of the compound represented by formula IV as a white powder. The yield is 85%, the purity...

Embodiment 2

[0085] Embodiment 2: the synthetic route of Tucatinib

[0086] In a 250mL flask, add the hydrochloride (5g, 34.4mmol, 1.0 equivalent) of the compound shown in formula VI, and 1-fluoro-2-methyl-4-nitrobenzene (5.32g, 34.4mmol, 1.0 equivalent) , DMF (100 mL), triethylamine (5.2 g, 51.6 mmol, 1.5 eq) and potassium hydroxide (2.9 g, 51.6 mmol, 1.5 eq). After the mixture was stirred at room temperature for 12-16 h, triethylamine (1.5 eq) and potassium hydroxide (1.5 eq) were added to react according to the remaining amount of the starting material until HPLC analysis showed that only less than 1% of the starting material remained. The total reaction time is less than 18h. The reaction mixture was poured into 500 g of ice and stirred for 2 h, a yellow precipitate formed. Filtration yielded a crude light yellow filter cake. The pure product was then obtained after recrystallization of the filter cake. The filter cake was dried under vacuum to obtain 5.64 g of the compound represe...

Embodiment 3

[0092] Example 3: The difference between this example and Example 2 lies in the synthetic route of the compound shown in formula VIII.

[0093] In a 25mL flask, add the hydrochloride (0.29g, 2mmol, 1.0 equivalent) of the compound shown in formula VI, and 1-fluoro-2-methyl-4-nitrobenzene (0.47g, 3mmol, 1.5 equivalent) , DMSO (6 mL), triethylamine (0.3 g, 3 mmol, 1.5 eq) and potassium hydroxide (0.17 g, 3 mmol, 1.5 eq). After the mixture was stirred at 70° C. for 8-12 h, triethylamine (1.5 eq) and potassium hydroxide (1.5 eq) were added according to the remaining amount of the starting material until HPLC analysis showed that only less than 1% of the starting material remained. The total reaction time does not exceed 18h. The reaction mixture was poured into 50 g of ice and stirred for 2 h, a yellow precipitate formed. Filtration yielded a crude light yellow filter cake. Then the filter cake was recrystallized and filtered to obtain 0.32 g of the compound represented by formu...

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Abstract

The invention discloses a synthesis method of Tucatinib, and the method comprises the following step: carrying out substitution reaction on halate of a compound shown in a formula VI or free alkali thereof serving as a raw material and a compound shown in a formula VII under an alkaline condition to obtain a compound shown in a formula VIII. The raw materials used in the whole synthesis route areeasy to obtain, expensive catalysts are not needed, and the method is suitable for large-scale production and beneficial to industrial production of the Tucatinib.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of tucatinib and its intermediate product. Background technique [0002] Tucatinib is a potent and selective oral tyrosine kinase inhibitor of HER2, a growth factor receptor overexpressed in a variety of cancers, including breast cancer, colorectal cancer, esophageal cancer, gastric cancer, Lung and ovarian cancer. It is overexpressed in about 20 percent of breast cancers and is safe and effective with standard therapy in patients with advanced HER2-positive breast cancer and those with brain metastases from their primary disease. Tucatinib has been evaluated as a single agent and in combination with other HER2-directed agents, including (trastuzumab) and (Trastuzumab). The results of the clinical phase 1b trial showed that the combination of tucatinib, capecitabine and trastuzumab was generally well tolerated and showed clinical activity in patien...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73C07D471/04
CPCC07D213/73C07D471/04
Inventor 王郁萱李智温进富姚志刚
Owner 宁波药腾医药科技有限公司
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