A preparing method of Idelalisib

A technology of purine and amino group is applied in the field of preparation of medicine idelanide, which can solve problems such as environmental pollution, and achieve the effects of easy availability of raw materials, economical and environmental protection of the process, and promotion of development.

Active Publication Date: 2015-01-07
优标易站(苏州)电子商务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this method also has some technical defects or weaknesses, such as raw materials such as 6-bromo-purine are difficult to obtain, the amino group in S-2-aminobutyric acid needs to be protected and deprotected, a

Method used

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  • A preparing method of Idelalisib
  • A preparing method of Idelalisib
  • A preparing method of Idelalisib

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Add R-2-hydroxybutyrate ethyl (II) (6.6g, 50mmol), methanesulfonyl chloride (6.3g, 55mmol) and dichloromethane 100mL into the reaction flask, cool down to 0°C, add three Ethylamine (5.6g, 55mmol) was kept at the temperature for 1 hour, raised to room temperature and stirred for 8-10 hours, and TLC detected that the reaction was complete. The reaction solution was washed successively with 10% acetic acid solution, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in 50 mL of N,N-dimethylformamide, and 6-amino -9H-purine (6.8g, 50mmol), heat up to 120°C, slowly add pyridine (4.0g, 50mmol) dropwise, continue to maintain the temperature at 120-130°C, stir for 2 hours, cool to room temperature, and pour the reaction solution into ice water, and extracted 3 times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, the s...

Embodiment 2

[0030] Add R-2-hydroxybutyrate benzyl (II) (1.9g, 10mmol), p-toluenesulfonyl chloride (2.1g, 11mmol) and 25mL of dichloromethane into the reaction flask, cool down to 0°C, add di Isopropylethylamine (1.4 g, 11 mmol) was kept at the temperature for 1 hour, then raised to room temperature and stirred for 6-8 hours, and the reaction was completed as detected by TLC. The reaction solution was washed successively with 10% acetic acid solution, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in 20 mL of N,N-dimethylformamide, and 6-amino -9H-purine (1.4g, 10mmol), heat up to 120°C, slowly add pyridine (0.8g, 10mmol) dropwise, continue to maintain the temperature at 120-130°C, stir for 3 hours, cool to room temperature, and pour the reaction solution into ice water, and extracted 3 times with dichloromethane, the organic phases were combined, dried over anhydrous so...

Embodiment 3

[0032] Add S-2-(N-9H-purin-6-yl)aminobutyric acid ethyl ester (III) (5.0g, 20mmol) and 50mL of dichloromethane into the reaction flask under nitrogen atmosphere, add 2M dichloromethane dropwise at 0°C 15 mL of n-hexane solution of trimethylaluminum, slowly rise to room temperature, dropwise add 15 mL of dichloromethane solution of 2-formic acid-3-fluoroaniline (3.1 g, 20 mmol), after the drop is completed, heat up to reflux, and react for 5-6 hours , TLC detected that the reaction was complete. After cooling, the reaction solution was poured into 15% sodium hydroxide solution, extracted three times with dichloromethane, the organic phases were combined, and dried over anhydrous magnesium sulfate. After concentration, the residue was recrystallized from methanol to obtain 6.6 g of beige solid S-2-(N-9H-purin-6-yl)amino-N-(2-formic acid-3-fluorophenyl)butyramide (IV). Yield 92.2%, EI-MS m / z 359 (M+H).

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Abstract

A preparing method of Idelalisib (I) is disclosed. The preparing method includes following steps of: subjecting R-2-hydroxybutyrate (II) and 6-amino-9H-purine to nucleophilic substitution under actions of a leaving agent and an acid-binding agent to produce an intermediate S-2-(N-9H-purin-6-yl)aminobutyrate (III); subjecting the intermediate (III) and 2-amino-6-fluorobenzoic acid to amidation under actions of a catalyst to produce S-2-(N-9H-purin-6-yl)amino-N-(2-carboxyl-3-fluorophenyl)butyramide (IV); subjecting the intermediate (IV) to a cyclization reaction in acetic anhydride; and performing a substitution reaction with phenylamine to obtain the Idelalisib (I). The preparing method has characteristics of easily available raw materials, simple and concise process, capability of being economical and environmental friendly, and suitability for industrial production.

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 Idelranib, a drug used for treating chronic lymphocytic leukemia. Background technique [0002] Idelalisib is a phosphoinositide 3-kinase inhibitor developed by Icos Corporation and Gilead Sciences. The drug was approved by the U.S. FDA in July 2014 for the treatment of 3 types of B-cell blood cancer: combined with rituximab for relapsed chronic lymphocytic leukemia (CLL), as a monotherapy for relapsed follicular B-cell non-Hodgkin Chickkin's Lymphoma (FL) and Relapsed Small Lymphocytic Lymphoma (SLL), under the brand name Zydelig. Because the medicine does not yet have a standard Chinese translation, the applicant transliterates it as "Aidrani" here. [0003] The chemical name of Idelalisib is: 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinolin Azo...

Claims

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Application Information

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IPC IPC(8): C07D473/34
CPCC07D473/34
Inventor 许学农
Owner 优标易站(苏州)电子商务有限公司
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