Method for preparing Alisertib

A technology of arisetide and methoxyphenyl, which is applied in the field of preparation of arisetide, can solve problems such as low reaction yield, difficult purification, and increased difficulty in industrialization, and achieves easy-to-obtain raw materials, simple process, Conducive to the effect of industrial production

Active Publication Date: 2013-11-27
临泉县联正电子商务有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the fact that the raw materials are not easy to obtain in the above reaction route, the total yield is low and poisonous catalysts such as mercuric sulfate need to be used, especially the reaction yield of ariseti (I) from the condensation of intermediate (IX) and intermediate (VI) Low, and difficult to purify, making it more difficult to industrialize

Method used

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  • Method for preparing Alisertib
  • Method for preparing Alisertib
  • Method for preparing Alisertib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] -20°C and dry nitrogen atmosphere, add sodium hydride (0.5g, 20mmol) and acetonitrile 5mL to the reaction flask, stir for 30 minutes and then slowly rise to 0°C, dropwise add 3-[(2-fluoro-6-methoxy Base) phenyl]-5-chlorophthalide (II) (2.92g, 10mmol) in acetonitrile 20mL solution, warmed up to room temperature, stirred for 24 hours, TLC detected the end of the reaction. Dichloromethane and water were added to quench the reaction, the organic phase was separated, the aqueous phase was adjusted to pH 7.5-8.5 with hydrochloric acid, and extracted three times with dichloromethane. Dry over anhydrous sodium sulfate, distill under reduced pressure to recover the solvent, and recrystallize the residue with dichloromethane and petroleum ether to obtain off-white solid 1,3-dihydro-1-hydroxy-3-[(2-fluoro-6-methanol) Oxy)phenyl]-5-chloro-isobenzofuran-1-acetonitrile (III) 2.10 g, yield 63.1%.

Embodiment 2

[0027] At room temperature, add 1,3-dihydro-1-hydroxyl-3-[(2-fluoro-6-methoxy)phenyl]-5-chloro-isobenzofuran-1-acetonitrile ( III) (1.67g, 5mmol) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) 15mL, heated up to 60-65°C, stirred for 18 hours, and TLC detected the end of the reaction. Unreacted N,N-dimethylformamide dimethyl acetal was removed under reduced pressure. After cooling down to room temperature, the reaction was quenched with water, extracted 3 times with dichloromethane, and dried. The solvent was recovered under reduced pressure to give crude oil 3-{[1-(4-chlorophenyl)-1'-(2-fluoro-6-methoxyphenyl)methanol]-2-yl}-2-[ 2-(Dimethylamino)methylene]-3-oxapropionitrile (IV) 1.75 g, yield 90.2%.

Embodiment 3

[0029] At room temperature, add 3-{[1-(4-chlorophenyl)-1'-(2-fluoro-6-methoxyphenyl)methanol]-2-yl}-2-[2 -(dimethylamino)methylene]-3-oxapropionitrile (IV) (1.94g, 5mmol), 4-guanidine-2-methoxybenzoic acid hydrochloride (VI) (1.27g, 6.25 mmol), potassium tert-butoxide (1.4g, 12.5mmol) and 50mL of methanol, the temperature was raised to reflux, stirred and reacted for 18 hours, and the reaction was detected by TLC. The reaction was quenched with water, adjusted to pH 1-2 with hydrochloric acid, and extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, the solvent was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate and n-hexane to obtain off-white solid 4-{[4-[1-(4-chlorophenyl)-1' -(2-fluoro-6-methoxyphenyl)methanol]-5-cyanopyrimidin-2-yl]amino}-2-methoxybenzoic acid (V) 2.08g, yield 77.9%.

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Abstract

The invention discloses a method for preparing Alisertib (I), which comprises the following steps: an addition reaction is carried out between 3-[(2-fluoro-6-methoxyl) phenyl]-5-chlorobenzene phthalein (II) and acetonitrile, so as to generate 1,3-dihydro-1-hydroxyl-3-[(2-fluoro-6-methoxyl) phenyl]-5-chloro-isobenzofuranone-1-acetonitrile (III); a condensation reaction is carried out between the intermediate (III) and N,N-dimethyl formamide-dimethylacetal (DMF-DMA), so as to generate 3-{[1-(4-chlorphenyl)-1'-(2-fluoro-6-methoxyphenyl) methanol]-2-group}-2-[2-(dimethylamino) methene]-3-oxa-propionitrile (IV); a cyclization reaction is carried out between the intermediate (IV) and 4-guanidine-2-methoxyl benzoate hydrochloride (VI), so as to generate 4-{[4-[1-(4-chlorphenyl)-1'-(2-fluoro-6-methoxyphenyl) methanol]-5-pyrimidine-carbonitrile-2-group] amino}-2-methoxyl benzoic acid (V); Alisertib (I) is obtained by reducing, oxidizing and cyclizing the intermediate (V). The method has the advantages that the process is easy; the raw materials are easy to obtain; the requirement for industrial magnification is met.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of Alisertib. Background technique [0002] Alisertib (codename MLN8237) is a multi-target small molecule compound jointly developed by Millennium and Takeda. Because the drug has not been officially marketed in my country and has no standard Chinese translation, the applicant transliterates it as "aliseti" here. Alisertib is an Aurora kinase (Aurora A), cell cycle and mitosis inhibitor. Scientific research shows that arisetinib is a milder anticancer drug without the huge side effects of conventional chemotherapy drugs. That's because the compound specifically targets a key enzyme, avoiding damage to healthy cells in the bone marrow and blood, and may be more effective at lower doses than drugs tested in previous studies. Phase III clinical studies based on the evaluatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 许学农
Owner 临泉县联正电子商务有限公司
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