Preparation method of Tucatinib intermediate

A technology of tucatinib and intermediates, which is applied in the field of organic synthesis and the preparation of raw materials, can solve the problems of low production efficiency, and achieve the effects of high production efficiency, mild reaction conditions, and easy availability of raw materials

Pending Publication Date: 2021-06-04
SHANGHAI FAMO BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to overcome the defects that the existing preparation method is difficult to enlarge the preparation and the production efficiency is too low, and provide a kind of raw material that is easy to get, the process is simple, the operation is convenient, the cost is low, and the yield is higher to prepare the tucatinib intermediate ( Specifically the 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline) method

Method used

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  • Preparation method of Tucatinib intermediate
  • Preparation method of Tucatinib intermediate
  • Preparation method of Tucatinib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] A preparation method of tucatinib intermediate, the steps are as follows:

[0031] (1) Preparation of N'-(4-chloropyridin-2-yl)-N-hydroxyl formamide (i.e. product I—compound N, hereinafter referred to as N):

[0032] 2-Amino-4-chloropyridine (L) (50.0g, 0.39mol) was added to ethanol (150mL), DMF-DMA (51.0g, 0.43mol) was added to the reaction solution, the reaction suspension was stirred and Heat to 60-70°C for 2 hours to obtain a light yellow solution, cool the resulting solution to about 40°C, then add hydroxylamine hydrochloride (33.0 g, 0.47 mol) to the reactant, stir the reaction solution and heat to 50-55 ℃ for 2h, the reaction solution was cooled to room temperature, diluted with 450mL of ice water, stirred for 1h, a solid was generated, filtered with suction, washed with ethanol (15mL×1), and dried at 55°C for 8h to obtain a white solid N (59.5g, 89.2%);

[0033] (2) Preparation of 7-chloro-[1,2,4]triazolo[1,5-a]pyridine (i.e. product II—compound O, hereinafter...

Embodiment 2

[0053] A preparation method of tucatinib intermediate, the steps are as follows:

[0054] (1) Preparation of N'-(4-chloropyridin-2-yl)-N-hydroxyl formamide (i.e. product I—compound N, hereinafter referred to as N):

[0055] 2-Amino-4-chloropyridine (L) (50.0g, 0.39mol) was added to ethanol (150mL), DMF-DMA (51.0g, 0.43mol) was added to the reaction solution, the reaction suspension was stirred and Heat to 60-70°C for 2 hours to obtain a light yellow solution; cool the obtained solution to about 40°C, then add hydroxylamine hydrochloride (33.0 g, 0.47 mol) to the reactant, stir the reaction solution and heat to 50-55 The reaction solution was reacted at ℃ for 2 hours; the reaction solution was cooled to room temperature, and then cooled in an ice-water bath for 1 hour to form a solid, which was filtered by suction, washed with ethanol (15mL×1), and dried at 55℃ for 8 hours to obtain white solid N (39g, 58%); The suction-filtered mother liquor was concentrated to 100 mL, 300 mL...

Embodiment 3

[0062] A preparation method of tucatinib intermediate, the steps are as follows:

[0063] (1) The preparation of N'-(4-chloropyridin-2-yl)-N-hydroxyformamide (i.e. product I—compound N, hereinafter referred to as N) is the same as that described in Example 1;

[0064] (2) The preparation of 7-chloro-[1,2,4]triazolo[1,5-a]pyridine (i.e. product II—compound O, hereinafter referred to as O) is the same as described in Example 2;

[0065] (3) Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (ie compound A, hereinafter referred to as A) It is the same as described in Example 1.

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Abstract

The invention discloses a preparation method of a tucatinib intermediate, which comprises the following steps: firstly, reacting 4-chloropyrido-2-amine with N,N-dimethylformamide dimethyl acetal, and then adding hydroxylamine hydrochloride for reaction to obtain a product I; reacting the product I with trifluoroacetic anhydride to obtain a product II; finally, carrying out heating reaction on the product II and 4-amino-2-methylphenol in a DMF / potassium carbonate system to prepare the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylaniline. According to the preparation method of the tucatinib intermediate, the raw materials are easy to obtain, and the production cost can be remarkably reduced; the whole process is simple, the whole time consumption is short, the production efficiency is high, the yield is high, the reaction condition is mild, the post-treatment is simple and convenient, and the method is suitable for large-scale preparation and has a great application prospect.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and preparation of raw materials, and relates to a preparation method of a tucatinib intermediate, in particular to an antitumor drug tucatinib intermediate 4-([1,2,4]three A new method for the preparation of azolo[1,5-a]pyridin-7-yloxy)-3-methylaniline. Background technique [0002] Tucatinib (its structural formula is as shown in the left side of formula I tucatinib), also known as irbinitinib, ARRY-380 or ONT-380, the trade name is Tukysa, is HER2 (human epidermal growth factor receptor tyrosine Oral inhibitor of the kinase ErbB-2). Developed by Seattle Genetics and approved by the US FDA on April 17, 2020, for the treatment of HER2+ breast cancer. [0003] [0004] In the chemical synthesis of tucatinib, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (A, whose structural formula is Shown in A on the right side of formula I) is its key intermediate. [0005] At prese...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 唐家邓王小梅茆勇军
Owner SHANGHAI FAMO BIOTECH CO LTD
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