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Preparation method of Fikatinib intermediate

A technology for intermediates and tinib, applied in the field of preparation of tucatinib intermediates, can solve the problem of high production cost, and achieve the effects of short reaction time, mild reaction conditions and reduced energy consumption

Pending Publication Date: 2022-07-01
上海蓝乐鸟实业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The method uses 2-amino-4-chloropyridine and 2-methyl-4-nitrophenol as raw materials to carry out the first step of nucleophilic substitution reaction, which needs to be reacted for 24 hours, and the total reaction time of the synthetic route needs at least 3 days , the final yield is only 40-60%, resulting in high production costs

Method used

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  • Preparation method of Fikatinib intermediate
  • Preparation method of Fikatinib intermediate
  • Preparation method of Fikatinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] A preparation method of a tucatinib intermediate, the intermediate is specifically 4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy)-3-methyl base aniline, the preparation method specifically comprises the steps:

[0029] S1: Add 100 mL of DMF and 39.4 g of benzenesulfonyl chloride to the reaction flask, stir to mix evenly, continue stirring for 30 to 40 minutes, add 23.9 g of 2-amino-4-chloropyridine, react at room temperature for 1.5 to 2.5 hours, and track by TLC After the reaction was complete, 33.11 g of a crude product of compound a was obtained after suction filtration, washing with ethyl acetate and drying.

[0030] S2: Mix the crude product of 33.11 g of the above-mentioned compound a with 15.09 g of hydroxylamine hydrochloride and 150 mL of 2mol / L sodium hydroxide solution in a reaction flask, stir at room temperature, and react after 50 to 60 minutes, after suction filtration and drying, to obtain 30.28 g of compound b, yield 95.2%.

[0031] S3: Mix 30.28 g of th...

Embodiment 2

[0034] A preparation method of a tucatinib intermediate, the intermediate is specifically 4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy)-3-methyl base aniline, the preparation method specifically comprises the steps:

[0035] S1: Add 86 mL of DMF and 36.21 g of benzenesulfonyl chloride to the reaction flask, stir to mix evenly, add 23.9 g of 2-amino-4-chloropyridine, react at room temperature for 3 to 4 hours, follow up with TLC until the reaction is complete, filter with suction, After washing with ethyl acetate and drying, 32.57 g of crude compound a was obtained.

[0036] S2: Mix the crude product of 32.57g of above-mentioned compound a with 17.30g of hydroxylamine hydrochloride and 145mL of 2mol / L sodium hydroxide solution in a reaction flask, stir at room temperature, react after 40 to 50 minutes, and after suction filtration and drying, obtain 29.41 g of compound b, yield 92.7%.

[0037] S3: Mix 29.41 g of the above-mentioned compound b with 200 mL of tetrahydrofuran in a...

Embodiment 3

[0040] A preparation method of a tucatinib intermediate, the intermediate is specifically 4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy)-3-methyl aniline, and steps S1 to S3 in the preparation method are the same as those in Example 1.

[0041]S4: Add 24.66g of pure compound c, 20.69g of 2-methyl-4-aminophenol, 46.55g of triethylamine and 150mL of NMP into the reaction flask, stir and heat to 110~125°C for reaction, reaction 15~16 hours, followed by TLC to complete the reaction. Ethyl acetate was added, the organic layer was washed with water and saturated sodium bicarbonate solution, the layers were separated, the solvent was removed from the organic phase by rotary evaporation, methanol and activated carbon were added, and after heating to reflux, cooling and filtration were performed to obtain 29.31 g of white solid, the target product 4- ([1,2,4]Triazolo[1,5-a]pyridine-7-alkoxy)-3-methylaniline, 76.2% yield.

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a ticatinib intermediate, which comprises the following steps: carrying out Vilsmeier reaction on raw materials 2-amino-4-halogenated pyridine, N, N-dimethylformamide and benzene sulfonyl chloride, reacting with hydroxylamine hydrochloride under alkaline conditions, then reacting with trifluoroacetic anhydride, and carrying out recrystallization to obtain the ticatinib intermediate. And finally, carrying out nucleophilic substitution reaction on the intermediate and 2-methyl-4-aminophenol in an alkaline solvent system to obtain a target product, namely, the Fikatinib intermediate. The preparation method only comprises four steps of reaction, the used raw materials and reagents are cheap and easy to obtain, the first step of Vilsmeier reaction and the second step of reaction can be carried out at room temperature, the reaction time is short, the reaction selectivity is good, and the reaction product can directly enter the next step of reaction. The reaction conditions are mild, and the reaction time is short, so that the energy consumption is greatly reduced; due to high selectivity of the reaction, the purification step is reduced, and the use of a large amount of reagents and the generated three wastes in post-treatment are avoided, so that the method is particularly suitable for large-scale industrial production.

Description

【Technical field】 [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a tucatinib intermediate. 【Background technique】 [0002] Tucatinib is a tyrosine kinase inhibitor jointly developed by Array BioPharma and Cascadian Therapeutics. It is used in combination with trastuzumab and capecitabine for the treatment of advanced unresectable or metastatic HER2-positive breast cancer. According to existing literature reports, the preparation route of tucatinib involves a key intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-alkoxy) -3-methylaniline, its structural formula is as follows: [0003] [0004] In the prior art, the preparation method of this key intermediate has the following synthetic routes: [0005] Method 1. The preparation route disclosed in patent WO2007059257 is as follows: [0006] [0007] This route uses 2-chloro-4-nitropyridine as raw material, undergoes nucleophilic substitution reaction with...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 钱小明丁芹肖小荣钱美
Owner 上海蓝乐鸟实业有限公司