Preparation method of Afuresertib

A reaction and amino technology, which is applied in the design of organic synthesis routes and the preparation of raw materials and intermediates, can solve the problems of lengthening reaction steps and affecting the final yield, and achieve the effects of quality improvement, simple process and mild conditions

Active Publication Date: 2020-09-04
济南健丰化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to avoid this competitive reaction, the existing synthetic routes have used the protection and deprotection of the amino group many times during the synthesis of intermediate A and the finished product FRESET, which makes the reaction steps longer and affects the final yield.

Method used

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  • Preparation method of Afuresertib
  • Preparation method of Afuresertib
  • Preparation method of Afuresertib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Add 3-fluorophenylacetaldehyde (II) (6.9g, 50mmol), (2R)-2-methoxymethyl-1-amino-tetrahydropyrrole (6.5g, 50mmol) and 100mL of benzene into the reaction flask, Under stirring, raise the temperature to 80-85°C, pass through the water separator until no water drops appear, and then react for 6 hours. Lowered to room temperature, washed with saturated brine, dried, and concentrated under reduced pressure to give light yellow oil (2R)-2-methoxymethyl-N-[2-(3-fluorophenyl)ethylidene]-1- Amino-tetrahydropyrrole (III) 8.7g, yield 69.6%, EI-MS m / z: 251[M+H] + .

Embodiment 2

[0044] Add titanium tetrachloride (40mL, 40mmol, 1.0M dichloromethane solution), (2R)-2-methoxymethyl-N-[2 -(3-fluorophenyl)ethylidene]-1-amino-tetrahydropyrrole (III) (5.0g, 20mmol) and dichloromethane 50mL, after stirring for 30 minutes, trimethylsilylnitrile (3.0g , 30mmol) in 30mL of dichloromethane solution, kept at low temperature for 12 hours, and slowly rose to room temperature. Washed successively with saturated ammonium chloride solution and water, dried, and concentrated under reduced pressure to obtain light yellow oil ((2R)-2-methoxymethyl-N-[(1S)-2-(3-fluorophenyl) Methyl-2-acetonitrile]-1-amino-tetrahydropyrrole (IV) 4.1g, yield 74.0%, EI-MS m / z: 278[M+H] + .

Embodiment 3

[0046] Add (2R)-2-methoxymethyl-N-[(1S)-2-(3-fluorophenyl)methyl-2-acetonitrile]-1-amino-tetrahydropyrrole to the hydrogenation reaction flask (IV) (2.8 g, 10 mmol), palladium on carbon (0.14 g, 5% w / w) and methanol 50 mL. At 25-30°C, according to the hydrogenation reaction procedure, hydrogen gas was introduced under normal pressure, and the reaction was stirred for 4-6 hours. The catalyst was recovered by filtration, and the solution was concentrated under reduced pressure to obtain 1.5 g of a light colorless oil (αS)-α-amino-3-fluorophenylpropionitrile (V), with a yield of 91.5%, EI-MS m / z: 165[ M+H] + .

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Abstract

The invention discloses a preparation method of Afuresertib. The preparation method comprises the following steps: firstly preparing a chiral compound (alpha S)-alpha-amino-3-fluorophenyl propionitrile, and carrying out amidation reaction and nitrile group reduction reaction on the chiral compound (alpha S)-alpha-amino-3-fluorophenyl propionitrile and 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid to obtain the target product Afuresertib. The preparation method is simple in process, mild in condition, optimized in environment, improved in quality and suitable for therequirement of industrial amplification.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of Afuresertib, an AKT kinase inhibitor. Background technique [0002] Afuresertib is an oral pan-AKT kinase inhibitor small molecule compound developed by Smithkline Beecham. Clinical trials have shown that the compound has shown single-drug activity against hematological malignancies and good safety and side effect controllability, and has good therapeutic effect for treating patients with advanced hematological malignancies including multiple myeloma. Clinical activity has also been observed in non-Hodgkin's lymphoma, Langerhans cell histiocytosis and Hodgkin's lymphoma. Because the drug has not been officially marketed in my country and has no standard Chinese translation, the applicant transliterates it as "Frisertib" here. [0003] The chemical name of Afuresertib is:...

Claims

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Application Information

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IPC IPC(8): C07D409/04
CPCC07D409/04
Inventor 许学农
Owner 济南健丰化工有限公司
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