A kind of preparation method of Acotinib

A technology of acotinib and a compound, applied in the field of preparation of acotinib, can solve the problems of difficult industrial operation, difficult purification, difficult to obtain, etc., and achieves a simple and efficient separation and purification method, short process steps, and simple operation. Effect

Active Publication Date: 2020-07-17
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Although the reaction route of the above scheme 2 is shorter, the raw materials 4-(pyridin-2-yl-aminocarbonyl)phenylboronic acid, [1-(1-oxo-2-butyn-1-yl)]-L-proline Amino acid and catalyst acetylacetonate rhodium dicarbonyl are expensive and difficult to obtain; and the intermediates involved need to be obtained by column chromatography, which is difficult to purify and difficult to industrialize.

Method used

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  • A kind of preparation method of Acotinib
  • A kind of preparation method of Acotinib
  • A kind of preparation method of Acotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: Preparation of N-(pyridin-2-yl)-4-cyanoacetylbenzamide (Ⅲ)

[0065] To a 500 ml four-neck flask connected with stirring, a thermometer, a reflux condenser and a dropping funnel, add 150 grams of tetrahydrofuran, 6.0 grams of acetonitrile, 16.8 grams (0.15 moles) of potassium tert-butoxide, between 30 and 35 ° C, drop Add 25.6 g (0.1 mole) of a mixture of N-(pyridin-2-yl) monomethyl terephthalate monoamide and 50 g of tetrahydrofuran, drop it, and react with stirring at 35 to 40° C. for 5 hours. Cool to 20 to 25°C, acidify the pH value of the system to 3.0-4.0 with 20wt% ammonium chloride aqueous solution, add 100 grams of dichloromethane, separate layers, and extract the aqueous layer with dichloromethane 3 times, 20 grams each time, combine the organic phase, dichloromethane was recovered by distillation to obtain 23.9 g of N-(pyridin-2-yl)-4-cyanoacetylbenzamide, the yield was 90.2%, and the liquid phase purity was 99.2%.

Embodiment 2

[0066] Example 2: Preparation of N-(pyridin-2-yl)-4-cyanoacetylbenzamide (Ⅲ)

[0067] To a 500 ml four-neck flask connected with stirring, a thermometer, a reflux condenser and a dropping funnel, add 150 grams of tetrahydrofuran, 6.0 grams of acetonitrile, 16.8 grams (0.15 moles) of potassium tert-butoxide, between 40 and 45 ° C, drop Add 27.0 g (0.1 mol) of a mixture of N-(pyridin-2-yl) monoethyl terephthalate monoamide and 50 g of tetrahydrofuran, drop it, and react with stirring at 40 to 45° C. for 4 hours. Cool to 20 to 25°C, acidify the pH value of the system to 3.0-4.0 with 20wt% ammonium chloride aqueous solution, add 100 grams of dichloromethane, separate layers, and extract the aqueous layer with dichloromethane 3 times, 20 grams each time, combine the organic phase, dichloromethane was recovered by distillation to obtain 24.1 g of N-(pyridin-2-yl)-4-cyanoacetylbenzamide, the yield was 90.9%, and the liquid phase purity was 99.1%.

Embodiment 3

[0068] Example 3: Preparation of N-(pyridin-2-yl)-4-cyanoacetylbenzamide (Ⅲ)

[0069] To a 500 ml four-neck flask connected with stirring, a thermometer, a reflux condenser and a dropping funnel, add 150 grams of tetrahydrofuran, 5.5 grams of acetonitrile, 10.0 grams (0.15 moles) of sodium ethylate, between 40 and 45 ° C, dropwise add 25.6 A mixture of gram (0.1 mole) of N-(pyridin-2-yl) monomethyl terephthalate monoamide and 50 grams of tetrahydrofuran was added dropwise, and stirred at 45 to 50° C. for 4 hours. Cool to 20 to 25°C, acidify the pH value of the system to 3.0-4.0 with 20wt% ammonium chloride aqueous solution, add 100 grams of dichloromethane, separate layers, and extract the aqueous layer with dichloromethane 3 times, 20 grams each time, combine the organic phase, dichloromethane was recovered by distillation to obtain 23.6 g of N-(pyridin-2-yl)-4-cyanoacetylbenzamide, the yield was 89.1%, and the liquid phase purity was 99.3%.

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Abstract

The invention provides an acalabrutinib preparation method, which comprises: carrying out a condensation reaction on N-(pyridine-2-yl)terephthalic acid monoester monoamide (II) and acetonitrile under the action of an alkali, carrying out a halogenation reaction with a halogenation reagent, carrying out a cyclization condensation reaction with [1-(1-oxo-2-butyne-1-yl)]-S-pyrrolidinyl-2-formamidine hydrochloride (V), carrying out a substitution reaction with 2-halogenated acetaldehyde diol, and carrying out cyclization in the presence of ammonium salt-ammonia to generate acalabrutinib (I). According to the present invention, the method has characteristics of short reaction route, simple steps, easy control of reaction conditions, low cost, high yield and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of acotinib, which belongs to the technical field of medicinal chemistry. Background technique [0002] Acotinib (I), known as Acalabrutinib in English, is a highly selective and irreversible second-generation BTK inhibitor developed by Acerta Pharma, a subsidiary of AstraZeneca. The drug can play a role by permanently binding BTK . Inhibits cancer cell growth signaling by blocking BTK until it promotes cancer cell death. In September 2015, the U.S. Food and Drug Administration (FDA) granted the drug orphan drug qualification for the treatment of mantle cell lymphoma. In March 2016, the European Medicines Agency (EMA) granted the drug orphan drug status for the treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma and lymphoplasmacytoid lymphoma. In November 2017, the FDA announced accelerated approval of acotinib for the treatment of adult patients with mantle cell l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 戚聿新王保林钱余峰刘月盛张明峰周立山
Owner XINFA PHARMA
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