Preparation method of Idelalisib

A compound and reaction technology, applied in the field of preparation of Idelalisib, to achieve the effects of easy availability, mild reaction conditions and high production efficiency

Inactive Publication Date: 2017-01-04
NANJING ANYUAN BIO PHARMA TECH CO LTD +1
View PDF8 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The method disclosed in CN104130261A is basically the same as the above-mentioned method, and the reaction conditions have been improved, but the above-mentioned problems have not yet been solved
[

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of Idelalisib
  • Preparation method of Idelalisib
  • Preparation method of Idelalisib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1 (S)-N-[2-[[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino]-1-ethyl-2-oxoethyl]-carbamic acid tertiary Preparation of butyl ester (compound of formula IV)

[0059] Dissolve N-BOC-L-2-aminobutyric acid (compound of formula III, 64g, 2eq) and N-methylmorpholine (35g, 2.2eq) in tetrahydrofuran (240mL), add isobutyl chloroformate dropwise at 0°C Ester (43g, 2.2eq), then dropwise into 2-amino-6-fluoro-N-phenylbenzamide (compound of formula II, 36g, 1eq) in tetrahydrofuran (300mL) solution, react at 60°C for 4 hours, and the reaction ends Then add saturated sodium bicarbonate solution, separate layers, take the lower aqueous solution and extract with ethyl acetate, wash the organic layer with saturated sodium chloride solution, concentrate to an oily substance, add n-hexane to make slurry and separate out 58g solid, yield: 90%, purity : 99% (area normalization method).

[0060] 1 HNMR (300MHz, CD 3 OD): δ H 8.08(1H, J=8.13),7.71(2H,J=7.98),7.48(1H,J=8.22),7.34(2...

Embodiment 2

[0063] Example 2 Preparation of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one (compound of formula V)

[0064] Dissolve the compound of formula IV (58g, 1eq) and iodine (36g, 1eq) in dichloromethane (675mL), add HMDS (89.5mL, 3eq), heat and reflux for 36 hours, and add 10% thio Sodium sulfate solution (500 mL) neutralized excess iodine, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to an oil, dissolved in ethyl acetate, and cooled to precipitate 28.7 g of solid. Yield: 70%, purity: 98.9% (area normalization method).

[0065] 1 HNMR (300MHz, CDCl 3 ):δ H 7.68(1H,m),7.52(4H,m),7.27(2H,m),7.09(1H,m),3.41(1H,dd,J=2.28,7.38),1.81(3H,m),1.50( 1H,m), 0.80 (3H,t,J=7.35).

[0066] 13 CNMR (75MHz, CDCl 3 ):δ C 161.4 (J C-F =264.8), 161.2, 149.5, 136.2, 134.7 (J C-F =10.5), 129.9, 129.7, 129.4, 129.0, 128.3, 123.1 (J C-F =4.5),113.2(J C-F =21.0), 54.3, 30....

Embodiment 3

[0068] Example 3 Preparation of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (compound of formula VIII)

[0069] Dissolve 6-chloropurine (19.9g, 1eq) in dichloromethane (199mL), add dropwise 2-hydropyran (16.3g, 1.5eq), react at 30°C for 2 hours, add the reaction solution into water, and separate layers , the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 27.7 g of solid, which was scraped off for later use. Yield: 90%, purity: 96% (area normalization method).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention belongs to the field of pharmaceutical and chemical engineering and specifically relates to a preparation method of Idelalisib. According to the preparation method, in the presence of hexamethyldisilazane and iodine, (S)-N-[2-[[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino]-1-ethyl-2-oxoethyl]-tert-butyl carbamate undergoes a reaction to prepare a key intermediate (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-ketone; and the key intermediate undergoes two-step reaction to finally obtain Idelalisib. The reaction reagents are easily available; reaction conditions are mild; operation is simple and the product is easy to prepare; production efficiency is high; the prepared intermediate and the product have high yield and high purity; and in comparison with the prior art, impurities are not easy to produce. Thus, the preparation method of the invention is especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of Idelalisib. Background technique [0002] Idelalisib, the chemical name is 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone (Formula Ⅰ) , is a novel highly selective PI3Kδ inhibitor developed by Gilead. The drug was approved by the U.S. FDA in July 2014 for the treatment of recurrent follicular B-cell non-Hodgkin's lymphoma (FL), recurrent small lymphocytic lymphoma (SLL) and combination therapy with rituximab Relapsed chronic lymphocytic leukemia (CLL). [0003] [0004] Currently, the synthesis of Idelalisib has been reported in the literature. WO2005113556 discloses the following preparation method, [0005] [0006] The method is to react 2-fluoro-6-nitro-N-phenylbenzamide with N-BOC-L-2-aminobutyric acid, and then undergo steps such as nitro reduction, cyclization, and deprotection, and the...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D473/34
CPCY02P20/55C07D473/34
Inventor 王小龙宋丰发顾巍朱善良刘飞刘彦龙张喜全顾红梅
Owner NANJING ANYUAN BIO PHARMA TECH CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap